Hematologic Malignancy

Chantrapa Sriswasdi, M.D. Hematology Unit, Phramongkutkloa Hospital

22 Nov 2009

Topics
Myeloproliferative neoplasms (MPNs) Acute myeloid leukemia Acute lymphoblastic leukemia Lymphoproliferative disorders Plasma cell dyscrasias

Myeloproliferative neoplasms (MPNs)

Common MPNs
Chronic myelogenous leukemia (CML), BCR-ABL +ve

Primary myelofibrosis (PMF)

Polycythemia vera (PV) Essential thrombocythemia (ET)

Characteristics of MPNs
Clonal hematopoietic stem cell disease
Overproduction of one or more blood cell lines

Organomegaly Extramedullary hematopoiesis Leukemic transformation Thrombosis: major cause of death

Complication
Leukemic transformation
Differ among the subgroups
CML >90% ET <5%

Thrombosis
Arterial and venous thrombosis
Mechanism: leukocyte, vascular endothelium, coagulation system

Microcirculatory disorder: erythromelalgia

Bleeding
High platelet count: acquired vWD

Erythrocytosis (Polycythemia)
Definition: Hct male > 52%,female > 48% Relative vs Absolute Absolute erythrocytosis
Hct male > 60%, female > 55%

Erythrocytosis (Polycythemia)
I. Relative or spurious erythrocytosis or Gaisbock's disease II. Absolute erythrocytosis
Primary marrow diseases: PV,1ry erythrocytosis
Reactive : increased EPO production

Erythrocytosis
Reactive : increased EPO production
Tissue hypoxia
Lung diseases : COPD Heart disease: Rt to Lt shunt High attitude Abnormal Hb, smoking Hypernephroma Hepatoma Cerebellar hemangioblastoma Uterine fibromyoma Polycystic kidney Renal artery stenosis

Tumors produce EPO

Renal diseases

Serum erythropoietin
Low Normal High

PV diagnosis probable
Bone marrow examination

PV diagnosis possible

Evaluate for secondary polycythemia

Characteristics for PV?

yes no

Specialized tests -JAK2 mutation -BM immunochemistry for c-mpl -PCR for PRV-1 gene -EEC formation
Mayo Clin Proc 2003;78:174-94.

PV

Specialized test Not consistent with PV

Consistent with PV

Reevaluate in 3 mo

Polycythemia vera
Increase RBC production independent of normal mechanisms Median age 60 years Mutation of Janus 2 kinase gene (JAK2 V617F) Panmyelosis 3 phases
Prepolycythemic phase Polycythemic phase Spent or post-polycythemic myelofibrosis

Pathogenesis
Disease Thrombosis

JAK2 mutation: MPNs

Reported in 2005 Mutation: JAK2V617F
Valine to Phenylalanine
Codon 617

Myeloprolifertive disorders
PV ET
MF

90-95% 50-70%
40-50%

Pathogenesis
Thrombosis High Hct Platelet
No correlation with platelet count Platelet defect
Increase platelet thromboxane A2 production Decrease response prostaglandin D2

Abnormal in vivo activation of leukocyte, endothelial cell Decrease natural anticoagulant Decrease fibrinolytic activity

Clinical features
Physical Findings Frequency (%) Symptoms Headache 48 Fatigue 47 Pruritus 43 Dizziness 43 Diaphoresis 33 Visual disturbances 31 Weight loss 29 Erythromelalgia 29 Dyspnea 26 Joint symptoms 26 Epigastric discomfort 24 thrombosis 20 Signs Splenomegaly 70 Skin plethora 67 Conjunctival plethora 59 Engorged vessels in the optic fluid 46 Hepatomegaly 40 Systolic blood pressure > 140 mmHg 72 Diastolic blood pressure > 90 mmHg 32
Semin Haematol 1975;12:339-51

Erythromelalgia

Burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis Microvascular thrombosis

WHO diagnostic criteria for PV

2 major + 1 minor or The first major + 2 minor

Laboratory
CBC Peripheral blood smear Bone marrow examination EPO level JAK2 mutation

CBC
Red cell Increase Hct, Hb Not increase in PV with iron deficiency White cell Leukocytosis Band form, metamyelocyte, myelocyte (Lt shift) Increase basophil, eosinophil Platelet Increase or normal

Blood smear
RBC: excess red cells, NC, NC hypochromic microcytic red cells (iron deficiency) WBC: increase with band form, myelocyte ,metamyelocyte Platelet: increase

Bone marrow smear

Hypercellular marrow Increase erythroid, myeloid, megakaryocyte (panmyelosis) Normal maturation of myeloid series M:E = 2-3:1 Increase megakaryocytes with different size Negative iron stain

Natural course
Survival
pre-phlebo non aggr phlebo Median sur 18 mo 3-4 yr Cause of death
Thrombosis Malignancy : acute leukemia, non-RE malignancy Myelofibrosis Bleeding

aggr phlebo 9-12.8 yr

Risk of thrombosis
Both PVSG and ECLAP
Old age: age > 60 years Previous thrombosis Phlebotomy treated group Other cardiovascular disease:
DM
Smoking

Polycythemia vera
Phlebotomy to maintain Hct < 45% male, <42% female

Low dose ASA

high risk of thrombosis Age>60 years Previous thrombosis Other cardiovascular risk Platelet > 1,500,000 /um

Age < 50 yr

Age 50-70 yr

Age > 70 yr

Interferon Hydroxyurea

Busulphan or 32P

Clue diagnosis PV
High Hct, absent secondary erythrocytosis Headache, plethora, thrombosis, pruritus Mild to moderate splenomegaly Hepatomegaly Leukocytosis, thrombocytosis Panmyelosis Low erythropoietin level JAK2 mutation

AMM
Other name
Chronic idiopathic myelofibrosis Myelofibrosis with myeloid metaplasia (MMM)

Atypical megakaryocytic hyperplasia

Produce cytokine to stimulate fibroblastic proliferation

AMM
Median age 67 years Symptoms
15-30% no symptom Severe fatigue ( anemia) Symptom due to enlarged spleen 5-20% weight loss, low grade fever, night sweats

Signs
Pallor Splenomegaly (>90%): marked, hallmark Hepatomegaly

Clinical features of AMM

Mechanism Hypercatabolic state Splenomegaly Anemia Portal hypertension/ascites Splenic infarct Esophageal varices/hemorrhoids Ectopic myeloid metaplasia Symptoms Fatigue, weight loss Pain, early satiety Dyspnea, palpitations Abdominal pressure, peripheral edema Acute left upper quadrant pain, fever GI bleeding Tumor mass effect (lung, GI, GU, CNS, spine/vertebral column) Thrombocytopenia/platelet dysfunction Bleeding, bruising Hyperuricemia Monoarticular arthritis, nephrolithiasis (synovitis, hematuria)

Laboratory findings
Anemia
Decrease production of bone marrow
Splenic sequestration

Bleeding from thrombocytopenia or varices Autoimmune hemolysis

Dilutional anemia

WBC: leukocytosis, leukopenia in progressive disease Platelet: thrombocytosis, thrombocytopenia

Laboratory findings
Blood smear
Teardrop red cell Anisopoikilocytosis Leukoerythroblastic blood picture Increase basophil Abnormal platelets Fragmented megakaryocyte

Laboratory findings
Bone marrow examination
Dry tap Marrow fibrosis with atypical megakaryocytic hyperplasia Increase alkaline phosphatase Increase LDH Increase uric acid Increase circulating CD34+ cells

Other lab tests

Causes of Marrow Fibrosis

Nonhematologic Hematologic Infections Myeloproliferative disorders ET, PV, MMM TB Leishmaniasis Hypereosinophilic Histoplasmosis syndrome HIV Systemic mastocytosis Connective tissue disease CML Renal osteodystrophy Other AML-M7 Metastatic cancer MDS Vitamin D deficiency Multiple myeloma Hypothyroidism Hairy cell leukemia Hyperthyroidism Lymphoma Paget disease ALL Gauchers disease Grey platelet syndrome

Treatment
Allogeneic stem cell transplantaio
Limit by age and HLA match 17% present age < 50 years

Androgens + corticosteroid (1 month) Danazol 200-800 mg/day Erythropoitin or blood transfusion Chemotherapy
Busulfan Hydroxyurea

Treatment
Splenectomy Splenic irradiation Anagrelide: for thrombocytosis Interferon Thalidomide+prednisolone (3 months)

Clue of Diagnosis
Clue for diagnosis
Elderly patients

Splenomegaly: moderate to huge size Teardrop red cells Leukoerythroblastic blood picture Dry tap with myelofibrosis

Essential Thrombocythemia (ET)

Essential thrombocythemia
Other named
Essential thrombocytosis Primary thrombocytosis

Diagnosis by
Excluding cause of reactive thrombocytosis Excluding other CMPDs

Female:Male = 2:1 Mean age at diagnosis 60 years

Clinical manifestation
50% asymptom Vasomotor symptom: thromboxane, microvascular thrombosis
Headache, lightheadedness, syncope Atypical chest pain, acral paresthesia Livedo reticularis, erythromelalgia Transient visual disturbances

Clinical manifestation
Thrombosis: common complication
Arterial site: stroke, TIA, retinal artery occlusion, coronary ischemia digital ischemia Venous site:DVT, PE, hepatic or portal vein

Hemorrhage: risk
Extreme thrombocytosis Use ASA > 325 mg/day Use NSAIDs

Clinical manifestation
Transformation
Myelofibrosis: 4% follow 9.2 years Acute myeloid leukemia
1.4% follow 9.2 years Previously treated by cytoreductive therapy

Physical examination
Splenomegaly 25-48%

WHO criteria for ET

Diagnosis requires all 4 criteria

Laboratory
PBS: RBC: NC,NC WBC: normal to mild leukocytosis Platelet: marked increase, vary in size, a few giant platelet Bone marrow smear: Hypercelularity Erythroid: adequate M:E= 3-4:1 Myeloid: adequate and normal maturation Megakaryocyte: numerous megakaryocytes, giant and hyperlobated nuclei

numerous megakaryocytes

giant and hyperlobulated nuclei

Reactive thrombocytosis
Iron deficiency, asplenia, malignancy, bleeding, hemolysis, infection, inflammation, connnective tissue disease Elevated acute-phase reactants
C-reactive protein Fibrinogen ESR Ferritin

Prognostic factors
Thrombotic events
6.6%/patient-year vs 1.2%/patient-year

Risk of thrombosis
History of previous thrombosis Age > 60 years Cardiovascular risk

No effect risk of thrombosis

Degree of thrombocytosis Abnormal platelet function

Risk factors
Low, Intermediate and High risk Low risk: have all of the followings
Age < 60 years No previous thrombosis Platelet < 1,500x 109/L No cardiovascular risk factors

High risk: have one or both

Age 60 years Previous thrombosis

Treatment
Near normal life expectancy Vasomotor symptom
Low dose ASA: 40-325 mg/day

Hydroxyurea Anagrelide Alpha interferon Pipobroman Radioactive phosphorus Busulfan

Treatment
Low risk
Low dose ASA

High risk
Cytoreductive : hydroxyurea
Low dose ASA

Clue diagnosis of ET
Increase platelet Asymptom, thrombosis, hemorrhage Increase megakarycytes with giant and hyperlobated nuclei Exclude reactive and other chronic MPN, MDS

Splenomegaly: causes
Congestive diseases
Cirrhosis Splenic vein thrombosis

Infection
Tuberculosis Virus, bacteria

Malignancy
Lymphoma Chronic MPD

Storage disease
Gaucher disease

Inflammatory disease
SLE Felty syndrome

Hemolytic anemia
Thalassemia AIHA

Miscellaneous
Tropical splenomegaly

Splenomegaly
Mild splenomegaly
< 2 cm below Lt costal margin

Massive splenomegaly
Extend to Lt lower quadrant

Moderate splenomegaly

Massive splenomegaly
Chronic myeloproliferative disorders Lymphoma, hairy cell leukemia Chronic lymphocytic leukemia Major thalassemia Gaucher disease Infection: TB, chronic malaria

Clonal disease Ph chromosome positive t(9;22) (q34;q11) p210BCR-ABL oncoprotein p190BCR-ABL related-monocytosis p230BCR-ABL related-prominent neutrophilic maturation, obvious thrombocytosis Mean age 50-60 yrs 3 phases: chronic, accelerated, blastic

CML

Clinical features of CML

Asymptom (20-40%) Fatigue, weight loss Splenomegaly: left upper quadrant abdominal pain, early satiety Bleeding

Priapism

WHO criteria
Accelerated phase CML
Blasts 10-19% in peripheral blood or marrow

Peripheral blood Ba 20% Thrombocytopenia : 100 x109/L

Thrombocytosis: 1,000 x109/L

Increase spleen: unresponse to treatment

Increase WBC: unresponse to treatment Cytogenetic evolution

WHO criteria
Blastic phase (myeloid or lymphoid)
Blasts 20% peripheral blood or marrow Extramedullary blast proliferation Large foci of blasts in marrow

Laboratory
Blood smear NC, NC, NRC Increase WBC, most are myeloid cells at varying stages of maturation, increase basophil and eosinophil % of blast and basophil Increase platelet

Marrow smear Hypercellularity Relatively increase erythoid M:E 10:1 Increase myeloid with all stages, increase Ba,Eo Increase small and hypolobated megakar. % blast

CML present with thrombocytosis

 58 abnormal CBC peripheral blood smear

Clue diagnosis
Age Leukocytosis, all stage of myeloid cells Increase basophil Splenomegaly WBC >30,000 /L Low neutrophil/leukocyte alkaline phosphatate (NAP or LAP) + Philadelphia chromosome: t(9;22) important for diagnosis

 Tyrosine kinase inhibitor

Therapy

disease control without cure imatinib, dasatinib, nilotinib

Allogeneic stem cell transplantation

Potential cure

Interferon alpha cytarabine Other cytoreductive agents (palliative)

Hydroxyurea Busulfan

Diagnosis chronic phase CML Candidate for myeloablative allogeneic SCT?

Yes; age < 40

Possibly, age 40-55

No; age > 55; medical contraindication

HLA-matched sibling or unrelated donor

HLA-matched sibling

No family donor

Imatinib mesylate Discuss imatinib vs. transplant If patient chooses imatinib close follow-up is required Q-PCR or FISH every 3 months BM cytogenetics every 12 months Partial response Increase dose of imatinib as tolerated Failed response Dasatinib,Nilotinib or SCT or experimental protocol

Acute myeloid leukemia

Risk of AML
Irradiation Benzene Chemotherapy
Alkalating agents Topoisomerase II inhibitor

MPNs MDS Genetic disorders: Down syndrome

Clinical manifestation
Median age 65 years Fever : prolong, acute Marrow failure: anemia, bleeding Tissue invasion: gum, skin, chloroma Life-threatening bleeding: DIC Hyperleukocytic syndrome: dyspnea, altered mental status

Clinical manifestation
Leukemia cutis syndrome or neutrophilic dermatosis
erythematous to violaceous tender nodules and plaques Neutrophil infiltrate

Uncommon organomegaly (monoblast)

Leukemia cutis
nodular and violaceous/gray-blue in color, no tender

Sweet syndrome
erythematous to violaceous tender nodules and plaques

Gum hypertrophy Severe gingivitis AML: monoblast Cyclosporin Dilantin Nifedipine Amyloidosis

Diagnosis
Blasts 20% in PB or BM
Myeloblast Monoblast/promonocyte Megakaryoblast

Blasts < 20% combined with

t(8:21) Inv(16), t(16;16) t(15;17)

FAB classification
M0 myeloblast MPO < 3% poor prognosis M1 myeloblast, without maturation M2 myeloblast with maturation M3 abnormal promyelocyte t(15;17) M4 myelomonoblast monocytic >20% M5 monoblast M6 erythroleukemia glycophorin A + M7 megakaryocytic acute myelofibrosis

Investigation
CBC, PBS Bone marrow exam Cytogenetic study Immunophenotype:
Flow cytometry

Biochemistry: LDH, uric acid, BUN, Cr, LFT

CBC
Decrease Hct, platelet WBC: increase with blast Pancytopenia
Severe Relative lymphocytosis Mimic aplastic anemia

Bone marrow aspiration

Hypercellular marrow Decrease megakaryocyte and erythroid series Increase blast, blast with granules, auer rods Myeloblast or monoblast 20%

Myeloblast with auer rods

Myeloblast

AML: M4

Monoblast

AML, M3

AML, M6

AML, M7

Prognostic factors
Patient age: good
< 40 years

Cytogenetics: good
t(8;21) t (15;17) Inv(16) or t(16;16)

Treatment
Remission induction
Cytarabine 7 days Anthracycline 3 days

Postremission therapy
Consolidation Intensive chemotherapy ; high DARC Stem cell transplantation

Acute promyelocytic leukemia

Increase abnormal promyelocytes t(15;17): PML RARa Hypergranular and microgranular types Hypergranular type: pancytopenia Microgranular type: high white cells

Acute promyelocytic leukemia

Hemorrhage- early death High cure rate compare with other AML subtype Coagulopathy
Disseminated intravascular coagulation Primary fibrinolysis Direct proteolysis

Investigation
CBC: leukocytosis, pancytopenia PBS D-dimer, coagulogram BUN, Cr Bone marrow exam Cytogenetic study Immunophenotype: flow cytometry

Hypergranular type
Abnormal promyelocyte with intense azurophilic granules Abnormal promyelocyte with numerous auer rods (faggot cells)

Microgranular type
Predominantly bilobed nuclear shape

Acute promyelocytic leukemia

All-trans retinoic acid:
Differentiated agent Target : RARa moiety

Arsenic trioxide (ATO)

Apoptosis Target: PML moiety

Acute promyelocytic leukemia

Treatment: front line
Induction
ATRA + anthracycline

Consolidation
Anthracycline

Maintenances (no benefit for molecularly negative

after consolidation )

ATRA+ Low dose chemotherapy 10% early death, 20-30% relapse

Acute promyelocytic leukemia Reduce bleeding or early death

Start ATRA before cytogenetic confirmation Maintain platelet 30,000-50,000 /L Fibrinogen level 150 mg/dL

Acute promyelocytic leukemia Differentiating (Retinoic acid) syndrome

Fever, dyspnea,fluid retention, weight gain, pleural or pericardial effusion, hypotension Dexamethasone

Acute promyelocytic leukemia Arsenic trioxide

Relapse or refractory APL Front line alone Front line : ATO+ATRA

Short duration for achieve CR (255 days)

Acute lymphoblastic leukemia

ALL
Younger age compare to AML Marrow failure Mild organomegaly CNS involvement Testicular involvement

Adverse prognostic factors

Age > 60 years WBC > 50,000 /mL Adverse cytogenetics
Ph chromosome + t(v;11q23) Trisomy 8 Hypodiploidy

Prolonged time to CR

FAB classification

ALL - L1 ALL - L2 ALL - L3

Treatment
Induction
Vincristine Glucocorticoid L-asperaginase Anthracycline

Consolidation CNS prophylaxis Maintenance therapy

Stem cell transplatation

Secondary remission High risk group
Ph+ ALL Undifferentiated phenotype High leukocyte count Long term to achieve CR

AML vs ALL
Clinical presentation
Age Previous malignancy Lymphadenopathy or splenomegaly

Morphology
Cytoplasmic granule: Auer rod Nuclear chromatin Nucleolus Dysplastic features

Lymphoblastic lymphoma
Young male Anterior mediastinal mass (75%)
Dyspnea, stridor, dysphagia, swelling of head and neck (SVC syndrome)

Involvement
Skin, bone, marrow, CNS, pleura

Most common T cell

ALL L2

ALL L3

 18 1 CXR: pleural Effusion pleural tapping and smear

Lymphoma
Non-Hodgin lymphoma Hodgkin lymphoma

Diagnostic test for lymphoproliferative disorders

Morphology Immunophenotyping Cytogenetics Molecular genetics

Classification of lymphoid neoplasm

B cell neoplasms
Precursor B-cell neoplasm Mature B-cell neoplasm

Hodgkin lymphoma
Nodular lymphocytepredominant Hodgkin lymphoma Classic Hodgkin lymphoma Nodular sclerosis
Mixed cellularity

T-cell and NK-cell neoplasms

Precursor T-cell neoplasm Mature (peripheral) T-cell neoplasms

NHL
Indolent NHL
Older age Present: organomegaly Advanced stage Long term survival Response to treatment but not curable Low constitutional symptom Follicular NHL : the most common type

Aggressive NHL
All age More acute presentation Present early stage

B symptom: fever
More curable Diffuse large B cell: the most common type

NHL
Indolent lymphoma
B cell
CLL/SLL Follicular grade I,II,IIIa Marginal zone MALT

Aggressive lymphoma
B cell
Mantle cell Follicular grade IIIb Diffuse large B cell Mediastinal large B cell Burkitt lymphoma

T cell
Mycosis fungoides/ Sezary syndrome Primary cutaneous ALCL

T cell
Systemic ALCL T-cell leukemia/ lymphoma

NHL

Approach to the diagnosis of NHL

Systemic complaints (B symptoms) Prolonged fever Lymphadenopathy Hepatosplenomegaly Specific organ involvement: testes, GI,CNS,lung Marrow involvement: anemia, bleeding Autoimmune manifestation History underlying disease: HIV, malignancy, Sjogren's syndrome

Emergency conditions
Conditions Spinal cord compression Pericardial tamponade SVC obstruction Hypercalcemia Hyperleukocytosis Acute airway obstruction Lymphomatous meningitis and/or CNS mass lesions Type of NHL Aggressive type Lymphoblastic lymphoma Primary mediastinum B cell NHL Aggressive type Lymphoblastic lymphoma Primary mediastinum B cell NHL Aggressive type

Emergency conditions
Conditions Hyperuricemia and tumor lysis syndrome Hyperviscosity syndrome
Intestinal obstruction, intussusception Ureteral obstruction Severe AIHA, ITP

Type of NHL Aggressive type

Waldenstrom's macroglobulinemia Aggressive type

Aggressive type B cell small lymphocytic lymphoma/CLL Venous thromboembolic disease Aggressive type Indolent type

Investigation in lymphoma
Confirm cell type
Immunophenotype: B or T cell

Prognosis
Staging: physical examination,CT abdomen, LDH

Associated disease
Anti HIV

Treatment-related mortality
LFT, BUN, Cr Hepatitis B virus

Aggressive NHL
Local LN enlargement > generalized LN enlargement Systemic symptoms Fever Anorexia and weight loss Organ involvement Liver : infiltrative lesion CNS: mass or meningeal involvement GI: stomach, colon Chest: anterior mediastinal mass Testis DDx: TB, SLE

Etiologic risk factors

Virus Bacteria Impaired immune Congenital Acquired EBV, HTLV-1, HHV-8, HCV Helicobactor pylori Ataxia telangiectasia Wiskott-Aldrich syndrome AIDS Post transplantation Autoimmune disease Herbicides

Environment

HIV and Lymphoma

3 types
Systemic NHL Primary CNS lymphoma Primary effusion lymphoma (PEL) or primary body cavity lymphoma

Aggressive type Large B cell type

Ann Arbor staging system

Stage I Single LN region (I) or single extranodal organ (IE) Stage II 2 nodal regions, same side of diaphragm Stage III Nodal involvement on both sides of diaphragm Stage IV Dissemination to extranodal organ A = asymptomatic, B = fever > 380 C, night sweats, Wt loss > 10% in 6 mo E = extranodal disease, X = bulky disease

Staging
Physical examination CT whole abdomen or other Bone marrow examination CT or MRI brain and LP
Burkitt or lymphoblastic lymphoma Large cell type involve
Bone marrow Testis sinonasal

Prognosis
IPI risk factors
Age > 60 years LDH > normal Performance status 2-4 Stage III or IV > 1 extranodal sites

Age-adjusted IPI (<60 yr)

LDH > normal Performance status 2-4 Stage III or IV

Treatment
Chemotherapy
Anthracycline-based regimen

Rituximab Radiotherapy
Reduced mass effect Combined with chemotherapy in 1st line for early stage

Post complete remission

Follow every 3 months : 2-3 years
Hx and physical exam CBC and LDH CT every 6 months

Follow every 4-6 months: year 4 and 5

Hx, physical exam CBC, LDH

Follow every 1 year: > year 5

NHL large cell type

Indolent B cell lymphoma

Follicular lymphoma grade I, II Marginal zone lymphoma

MALT lymphoma
CLL/SLL

Indolent B cell lymphoma

Old age Generalized lymphadenopathy Advanced stage: marrow involve Autoimmune cytopenia

MALT lymphoma
Location Gastric: most common Intestine Lung, salivary gland, thyroid, periorbital Associated with
H. pylori Sjgren syndrome Hashimoto thyroiditis

Lymphoplasmacytic lymphoma
+ monoclonal IgM = Waldenstrm macroglobulinemia Mature plasmacytoid lymphocyte Present
Anemia, lymphadenopathy Purpura, splenomegaly Hyperviscosity Tissue deposit of IgM: neuropathy, amyloidosis

Rouleaux formation

Lymphoplasmacytoid lymphocyte

CLL
The most common leukemia in the western country Old age: 60-65 years Increase skin, lung and GI cancers B cell malignancy CD19, CD20, CD5, CD23 positive FMC7 negative

Clinical presentation
Old age Asymptom Lymphadenopathy Hepatosplenomegaly Infection Immune cytopenia: AIHA, ITP

Diagnostic criteria
Sustained lymphocyte count 10,000 /L If lymphocyte count 10,000 /L + monoclonal B cell phenotype

Rai clinical staging system

Risk group, stage Low risk Stage 0 Features Med surv. (mo)

Blood and marrow lymphocytosis (L)

L + adenopathy L+ splenomegaly or hepatomegaly

> 120

Intermediate risk Stage I Stage II

High risk Stage III Stage IV

108 94

L+anemia (Hb<11 g/dL) L+thrombocytopenia (100,000/L)

60 60

Treatment
Chronic but incurable No treatment for
Early stage No symptom

Criteria for treatment

Worsening of constitutional symptom Progressive symptomatic adenopathy or hepatosplenomegaly Cytopenia Recurrent infection Short doubling time of blood lymphocytes

Treatment
Alkalating agents: chlorambucil, CVP Fludarabine : infection, AIHA Monoclonal antibody therapy
Alemtuzumab : anti CD52 Rituximab : anti CD20, low CD20 density

Blood smear, CLL

Bone marrow, CLL

CLL with AIHA

Multiple myeloma

Clinical presentation
Presentation General
Hematology

Symptom and sign Fatigue, anorexia, weight loss

Anemia : chronic, NCNC, macrocytic anemia Bleeding : platelet, coagulation, vessel pancytopenia

Orthopedics

Bone pain: back, chest Pathological facture

Clinical presentation
Presentation Neurology Symptom and sign Radiculopathy : thoracic, lumbosacral area Cord compression Peripheral neuropathy: Amyloid Paraneoplastic syndrome POEMS syndrome Alteration of consciousness Hypercalcemia Hyperviscosity

Clinical presentation
Presentation Infection Symptom and sign Bacteria: hypogammaglobulin, neutropenia, steroid Pneumonia Septicemia
Renal failure Proximal RTA Amyloidosis: nephrotic syndrome

Nephrology

Clinical presentation
Rare presentation
Prolonged fever Lymphadenopathy Hepatosplenomegaly CNS involvement

Laboratory findings
CBC , PBS
Cytopenia: anemia Rouleaux formation 50%, (polyclonal, monoclonal) Plasma cell in PBS

Demonstrate monoclonal protein

Protein electrophoresis (PEP) Immunoelectrophoresis (IEP) Immunofixation Serum free light chain

Reciprocal Ig changes

Total protein 13 mg% IgG 8280 mg% (650-1500) IgA 19 mg% (80-310) IgM 40 mg% (55-300) total = 8339 mg% IEP. Monoclonal IgG, k type, IgM, IgA, decrease

Total protein 7 mg% IgG 879 mg% (650-1500) IgA 70 mg% (80-310) IgM 52 mg% (55-300) total = 1001 mg% IEP. light chain disease Bence Jones protein

Laboratory findings
Imaging
Bone survey:
diffuse osteopenia punched-out lytic lesion

Bone scan
Technetium-99m Detect osteoblastic activity Should not be used

Diagnostic criteria for MM

International myeloma working group
Presence of M-protein

Bone marrow plasma cell > 10% or plasmacytoma

Presence of organ damage (one of following)
Increased serum Ca Renal failure (Cr > mg/mL)
Anemia Lytic bone lesion

Dx = all criteria

International staging system

Stage I Parameters Median survival
(months)

I
II III

2 microglobulin < 3.5 mg/L

and albumin > 3.5 g/dL Neither stage I nor III 2 microglobulin > 5.5 mg/L

62
44 29

Prognosis
Cytogenetics
Prognosis Poor Abnormal cytogenetics t(4;14)(p16;q32) t(14;16)(q32;q23) -17p13 Median survival (months) 25

intermediate
Good

-13q14
All others

42
50

Treatment
Specific treatment Chemotherapy
Alkalating agents

Thalidomide or lenalidomide
MP, MPT, Thal+dex, VAD, Len+dex

Autologous transplantation
Thalidomide maintenance

Bortezomib
Alone, +dex and doxorubicin

Treatment
Supportive treatment
Hypercalcemia Hyperviscosity syndrome Prevent fracture
Bisphosphonates: pamidronate, zolendronate

Radiation
Pain Cord compression