Hematology Rivas2008 Lecture4&5

Clonal Disorders of hematopoietic stem cells

Clonal Disorders of hematopoietic stem cells

Antonio Rivas PA-CAntonio Rivas PA-C

Objectives Objectives

Become familiar with pathogenesis, epidemiology, diagnosis and treatment of : Thrombosis-DVT Myelodisplastic Syndromes Myeloproliferative disorders Chronic Myeloid Leukemia Acute Leukemias : AML , ALL Neutropenia

Become familiar with pathogenesis, epidemiology, diagnosis and treatment of : Thrombosis-DVT Myelodisplastic Syndromes Myeloproliferative disorders Chronic Myeloid Leukemia Acute Leukemias : AML , ALL Neutropenia

Arterial-thrombosisArterial-thrombosis

Commonly related to coronary artery disease (ruptured atherosclerotic plaque)

Atherombolic disorder (ischemic stroke)

Commonly related to coronary artery disease (ruptured atherosclerotic plaque)

Atherombolic disorder (ischemic stroke)

Thrombosis Thrombosis

Virchow’s triad-defines mechanism underlying thrombosis Diminished blood flow Damage to the vascular wall Imbalance favoring procoagulants over anticoagulants

Virchow’s triad-defines mechanism underlying thrombosis Diminished blood flow Damage to the vascular wall Imbalance favoring procoagulants over anticoagulants

Thrombosis Thrombosis Data shows unique regulation of hemostasis in different vascular beds:

Cong.deficiency of ATIII, protein C or protein S lead to:

DVT of lower extremities, but not upper Inherited hypercoagulable disorders associated with factor V Leiden and the prothrombin G20210A mutation

produce DVT of the lower extremities and venous thrombosis of the brain

Data shows unique regulation of hemostasis in different vascular beds:

Cong.deficiency of ATIII, protein C or protein S lead to:

DVT of lower extremities, but not upper Inherited hypercoagulable disorders associated with factor V Leiden and the prothrombin G20210A mutation

produce DVT of the lower extremities and venous thrombosis of the brain

Atherothrombosis- Endothelial

Damage Atherothrombosis- Endothelial

Damage Associated with increased levels of Homocysteine(HCY) in congenitals syndromes, with damage to the vascular endothelium and downregulation of the Ecs anticoagulant functions

Increased HCY levels in people with deficiency in the cofactors for HCY metabolism: B6,B12,and Folates

Associated with increased levels of Homocysteine(HCY) in congenitals syndromes, with damage to the vascular endothelium and downregulation of the Ecs anticoagulant functions

Increased HCY levels in people with deficiency in the cofactors for HCY metabolism: B6,B12,and Folates

Atherothrombosis - Platelets

Atherothrombosis - Platelets

Platelet activation and adherence critical to the development of the thrombus

Anti-platelet therapy : Aspirin-inhibits COX - blocks TXA2 release Clopidogrel(Plavix) - block ADP receptors in Plts, used with ASA to prevent ischemic stroke

Abciximab/Integrilin/Aggrastat - block plts receptors from binding with Fibrinogen and vWF

Platelet activation and adherence critical to the development of the thrombus

Anti-platelet therapy : Aspirin-inhibits COX - blocks TXA2 release Clopidogrel(Plavix) - block ADP receptors in Plts, used with ASA to prevent ischemic stroke

Abciximab/Integrilin/Aggrastat - block plts receptors from binding with Fibrinogen and vWF

Thrombosis-DVTThrombosis-DVT

Inherited: recurrent thrombosis at early age, unusual sites, or family history

Adquired : systemic disorders ( autoimmune hemolytic anemia), collagen vascular disease(vasculitis), malignant disease

Inherited: recurrent thrombosis at early age, unusual sites, or family history

Adquired : systemic disorders ( autoimmune hemolytic anemia), collagen vascular disease(vasculitis), malignant disease

Risk Factors for Venous Thrombosis

Risk Factors for Venous Thrombosis

Inherited Factor V Leiden Prothrombin G20210A Deficiency of natural anticoagulant proteins

Inherited Factor V Leiden Prothrombin G20210A Deficiency of natural anticoagulant proteins

Inherited risk factors for DVT

Inherited risk factors for DVT

Factor V Leiden mutation -most common inherited disorder causing DVT

Activated protein C unable to inactivate factor V mutation with increased formation of thrombin

Factor V Leiden mutation -most common inherited disorder causing DVT

Activated protein C unable to inactivate factor V mutation with increased formation of thrombin

Heterozygous in 5% of the population with five fold increased risk for DVT-PE

Homozygous less frequent, with 90% increased risk for DVT

Weak hypercoagulable risk DVT-PE usually Associated to concomitant acquired factors: pregnancy, immobilization and oral contraceptives

Heterozygous in 5% of the population with five fold increased risk for DVT-PE

Homozygous less frequent, with 90% increased risk for DVT

Weak hypercoagulable risk DVT-PE usually Associated to concomitant acquired factors: pregnancy, immobilization and oral contraceptives

Prothrombin G20210A Mutation

Prothrombin G20210A Mutation

Mutation leads to increased prothrombin levels

Two-fold increased risk for DVT

3% European-derived population Diagnosis examining DNA for mutation

Mutation leads to increased prothrombin levels

Two-fold increased risk for DVT

3% European-derived population Diagnosis examining DNA for mutation

Inherited deficiency of natural anticoagulant proteins

Inherited deficiency of natural anticoagulant proteins

ATIII, protein C, protein S Less common than previous ones More likely to produce symptomatic venous thrombosis at early age

Accounts for fewer than 5-10% of all patients with DVT/PE

Functional and Antigenic Assays (quant/qualt-deficiencies)

ATIII, protein C, protein S Less common than previous ones More likely to produce symptomatic venous thrombosis at early age

Accounts for fewer than 5-10% of all patients with DVT/PE

Functional and Antigenic Assays (quant/qualt-deficiencies)

Acquired risk factors for DVT Surgery-TraumaAcquired risk factors for DVT Surgery-Trauma Surgery-orthopaedic-trauma: associated with immobilization and stasis of lower extremities blood flow

Also associated with fat embolism and tissue damage(massive TF release)

More than 50% incidence of DVT Prophylactic-temporary IVC filters used

to protect from PE in these cases

Surgery-orthopaedic-trauma: associated with immobilization and stasis of lower extremities blood flow

Also associated with fat embolism and tissue damage(massive TF release)

More than 50% incidence of DVT Prophylactic-temporary IVC filters used

to protect from PE in these cases

Other Acquired risk factors for DVT

Other Acquired risk factors for DVT

Pregnancy increases risk of DVT 5 fold(venous stasis and altered coagulation factors)

Oral Contraceptives /hormonal changes, increased risk for smokers

Prothrombotic states Nephrotic syndromes-loss of ATIII through the kidneys

Blood cell destruction-exposure of procoagulant membrane phospholipids (artificial heart valves, hemolytic anemias, sickle cell disease)

HIT, TTP-increased Plt activation and clearance Myeloproliferative disorders-increased aggregability of the Plts

Pregnancy increases risk of DVT 5 fold(venous stasis and altered coagulation factors)

Oral Contraceptives /hormonal changes, increased risk for smokers

Prothrombotic states Nephrotic syndromes-loss of ATIII through the kidneys

Blood cell destruction-exposure of procoagulant membrane phospholipids (artificial heart valves, hemolytic anemias, sickle cell disease)

HIT, TTP-increased Plt activation and clearance Myeloproliferative disorders-increased aggregability of the Plts

Antiphospholipid Antibody Syndrome

Antiphospholipid Antibody Syndrome

APA Syndrome acquired prothrombic disorder

Primary or Secondary to autoimmune Dis.SLE

Recurrent venous or arterial thrombosis, thrombocytopenia, fetal loss

Anticardiolipin Abs / Lupus anticoagulant present in serum

Antibodies directed against phospholipid - binding proteins such as:

Beta 2 glycoprotein I Prothrombin

APA Syndrome acquired prothrombic disorder

Primary or Secondary to autoimmune Dis.SLE

Recurrent venous or arterial thrombosis, thrombocytopenia, fetal loss

Anticardiolipin Abs / Lupus anticoagulant present in serum

Antibodies directed against phospholipid - binding proteins such as:

Beta 2 glycoprotein I Prothrombin

DVT general considerationsDVT general

considerations More frequent - Deep veins of the lower extremities and pelvis

80% arise in the deep calf veins Development up to 2 weeks post - operatively

Higher incidence in Total Hip replacement surgery

Half patients has no symptoms in early stage

More frequent - Deep veins of the lower extremities and pelvis

80% arise in the deep calf veins Development up to 2 weeks post - operatively

Higher incidence in Total Hip replacement surgery

Half patients has no symptoms in early stage

DVT-Symptoms / SignsDVT-Symptoms / Signs Dull ache - tight feeling - frank pain in the calf or whole leg, worse with walking (leg claudication)

Slight swelling calf muscle Distention superficial veins Slight fever and tachycardia Occlusion of femoral and iliac veins more symptomatic

Severe obstruction: cyanosis skin, and marked swelling

Dull ache - tight feeling - frank pain in the calf or whole leg, worse with walking (leg claudication)

Slight swelling calf muscle Distention superficial veins Slight fever and tachycardia Occlusion of femoral and iliac veins more symptomatic

Severe obstruction: cyanosis skin, and marked swelling

DVT-DiagnosisDVT-Diagnosis

Doppler Ultrasonography-test of choice

Respiratory/cardiac symptoms -V/Q scan, spiral CT scan chest - to exclude PE

On Physical Exam patients may have pain in the affected calf muscle with Dorsi-flexion of the foot (Homan’s sign)

Doppler Ultrasonography-test of choice

Respiratory/cardiac symptoms -V/Q scan, spiral CT scan chest - to exclude PE

On Physical Exam patients may have pain in the affected calf muscle with Dorsi-flexion of the foot (Homan’s sign)

DVT-Laboratory TestDVT-Laboratory Test

Evaluate for hereditary and acquired hyper-coagulable state specially young patients W/O predisposing event

Coagulation Profile, protein S, protein C, DNA-testing for factor V Leiden and prothrombin mutations

Anti-phospholipids Abs, Lupus Anticoagulant, ANA

Evaluate for hereditary and acquired hyper-coagulable state specially young patients W/O predisposing event

Coagulation Profile, protein S, protein C, DNA-testing for factor V Leiden and prothrombin mutations

Anti-phospholipids Abs, Lupus Anticoagulant, ANA

DVT-Diff.Dx.DVT-Diff.Dx. Calf muscle strain or contusion, difficult

Cellulitis where you might find a wound and inflammation is more striking

Lymphatic obstruction by tumor is usually painless and chronic

Acute arterial obstruction is more painful, absent peripheral pulses, no swelling present

Heart, Kidney, or liver disease edema is bilateral

Ruptured Baker’s cyst, history of arthritis in the same side knee

Calf muscle strain or contusion, difficult

Cellulitis where you might find a wound and inflammation is more striking

Lymphatic obstruction by tumor is usually painless and chronic

Acute arterial obstruction is more painful, absent peripheral pulses, no swelling present

Heart, Kidney, or liver disease edema is bilateral

Ruptured Baker’s cyst, history of arthritis in the same side knee

DVT-ProphylacticDVT-Prophylactic Elevation of the legs 15-20 degrees intra and post-operatively with knees slightly flexed

Intermittent pneumatic compression of the legs(sequential compressions devices)

Elastic anti-phlebitic stockings Walking briefly but regularly after surgery, or during long airplane and automobile trips

Anticoagulants-low dose Heparin 5000 units every 8-12 hrs subcutaneously

Elevation of the legs 15-20 degrees intra and post-operatively with knees slightly flexed

Intermittent pneumatic compression of the legs(sequential compressions devices)

Elastic anti-phlebitic stockings Walking briefly but regularly after surgery, or during long airplane and automobile trips

Anticoagulants-low dose Heparin 5000 units every 8-12 hrs subcutaneously

DVT-TreatmentDVT-Treatment Mandatory anticoagulant therapy in most cases to decrease the risk of PE UHT- bolus titrated to achieve a PTT 1.5-2.0 times baseline-requires hospitalization, 4 days or more

LMWH-subcutaneous Warfarin started within 24hrs to achieve INR 2.0-2.5 for at least 2 consecutive days before stopping heparin

1rst episode - treat for 6 months 2nd episode - variable 3rd episode - lifelong, also if the trigger factor for the thrombosis is chronic (CHF,inherited disorder)

Mandatory anticoagulant therapy in most cases to decrease the risk of PE UHT- bolus titrated to achieve a PTT 1.5-2.0 times baseline-requires hospitalization, 4 days or more

LMWH-subcutaneous Warfarin started within 24hrs to achieve INR 2.0-2.5 for at least 2 consecutive days before stopping heparin

1rst episode - treat for 6 months 2nd episode - variable 3rd episode - lifelong, also if the trigger factor for the thrombosis is chronic (CHF,inherited disorder)

Thrombolytic TherapyThrombolytic Therapy Streptokinase, Urokinase and TPA

Risk of therapy :local and generalized bleeding, intracraneal hemorrhage

Patients without complications return to their routine in 3-6 weeks after appropriate treatment

Streptokinase, Urokinase and TPA

Risk of therapy :local and generalized bleeding, intracraneal hemorrhage

Patients without complications return to their routine in 3-6 weeks after appropriate treatment

Myelodysplastic SyndromeMyelodysplastic Syndrome

heterogeneous ineffective and disordered hematopoiesis affects myeloid cell lines one or more cytopenias Disordered maturation and increased

intramedullary apoptosis (programmed cell death)

decreased mature cells into the periphery normal or increased hematopoietic cells in the

bone marrow

heterogeneous ineffective and disordered hematopoiesis affects myeloid cell lines one or more cytopenias Disordered maturation and increased

intramedullary apoptosis (programmed cell death)

decreased mature cells into the periphery normal or increased hematopoietic cells in the

bone marrow


1 in 500 patients between the ages of 60 and 75 years

Most idiopathic , 25 % overall risk of transformation to acute myelogenous or myeloid leukemia

Exposure to radiation, chemotherapy, and organic chemicals (benzene) increase risk of MDS.

Secondary MDS, after treatment for other cancers, may occur at any age ,comprises 10% to 15% of all MDS cases.

1 in 500 patients between the ages of 60 and 75 years

Most idiopathic , 25 % overall risk of transformation to acute myelogenous or myeloid leukemia

Exposure to radiation, chemotherapy, and organic chemicals (benzene) increase risk of MDS.

Secondary MDS, after treatment for other cancers, may occur at any age ,comprises 10% to 15% of all MDS cases.


Pat. referred for evaluation of incidental cytopenias

If Symptomatic ,bleeding and bruising, infection, or fatigue and dyspnea related to anemia

PExam occasional splenomegaly, development of skin lesions with fever (acute febrile neutrophilic dermatosis, or Sweet's syndrome) may herald transformation of MDS into acute leukemia.

Pat. referred for evaluation of incidental cytopenias

If Symptomatic ,bleeding and bruising, infection, or fatigue and dyspnea related to anemia

PExam occasional splenomegaly, development of skin lesions with fever (acute febrile neutrophilic dermatosis, or Sweet's syndrome) may herald transformation of MDS into acute leukemia.

Myelodysplastic Syndrome-Lab.Studies

Myelodysplastic Syndrome-Lab.Studies

Erythroid cells macrocytic, often with basophilic stippling.

Neutrophils hypogranular and hypolobulated, bilobed nucleus, pseudo-Pelger-Huet abnormality.

Bone marrow : normo-hypercellular, dysplastic changes in all three cell lines Shift to the left Micro-megakariocytes / hypogranular blasts

Erythroid cells macrocytic, often with basophilic stippling.

Neutrophils hypogranular and hypolobulated, bilobed nucleus, pseudo-Pelger-Huet abnormality.

Bone marrow : normo-hypercellular, dysplastic changes in all three cell lines Shift to the left Micro-megakariocytes / hypogranular blasts

World Health Organization Classification of Myelodysplastic Syndromes

World Health Organization Classification of Myelodysplastic Syndromes

Refractory Anemia (RA) Ra with Ringed Sideroblasts (RARS) Ref.Cytopenia with Multilineage Dysplasia (RCMD)

RC with MD and RS (RCMD-RS) RA with excess Blasts 1 (RAEB-1) RA with excess Blasts 2 (RAEB-2) Myelodysplastic Syndrome Unclassified (MDS-U)

MDS associated with isolated del(5q)

Refractory Anemia (RA) Ra with Ringed Sideroblasts (RARS) Ref.Cytopenia with Multilineage Dysplasia (RCMD)

RC with MD and RS (RCMD-RS) RA with excess Blasts 1 (RAEB-1) RA with excess Blasts 2 (RAEB-2) Myelodysplastic Syndrome Unclassified (MDS-U)

MDS associated with isolated del(5q)


Median survival is usually less than 2 years

15 - 20% of patients die of AML Treatment is limited and dictated by

age, performance status, quality of life, severity of disease, and prognostic category

Most managed supportively

Median survival is usually less than 2 years

15 - 20% of patients die of AML Treatment is limited and dictated by

age, performance status, quality of life, severity of disease, and prognostic category

Most managed supportively

Myelodysplastic Syndrome treatment

Myelodysplastic Syndrome treatment

Chronic RBC / Plt transfusion- iron overload-secondary hemochromatosis

EPO, G-CSF reduce transfusion needs In patients with high risk transformation to AML- Chemotherapy

Only curative therapy- allogeneic stem cell transplant(<40 years of age)

Immune-suppresive therapy has been used (cyclosporin,thalidomide)

Chronic RBC / Plt transfusion- iron overload-secondary hemochromatosis

EPO, G-CSF reduce transfusion needs In patients with high risk transformation to AML- Chemotherapy

Only curative therapy- allogeneic stem cell transplant(<40 years of age)

Immune-suppresive therapy has been used (cyclosporin,thalidomide)

Chronic Myeloproliferative Disorders

Chronic Myeloproliferative Disorders

Clonal stem cell disorders Leukocytosis, thrombocytosis, erythrocytosis,

splenomegaly, and bone marrow hypercellularity

Failure to respond to normal feedback mechanisms regulating cell mass

Stem cells demonstrate clonal colony growth in vitro in the presence of serum without the addition of exogenous cytokines

Clonal stem cell disorders Leukocytosis, thrombocytosis, erythrocytosis,

splenomegaly, and bone marrow hypercellularity

Failure to respond to normal feedback mechanisms regulating cell mass

Stem cells demonstrate clonal colony growth in vitro in the presence of serum without the addition of exogenous cytokines

Chronic Myeloproliferative Disorders Polycythemia

Vera (PV)

Chronic Myeloproliferative Disorders Polycythemia

Vera (PV) Absolute erythrocytosis Half of the patients have leukocytosis and/or thrombocytosis

Clonal genetic abnormalities in marrow cells

No causes of secondary erythrocytosis

Low serum EPO levels Palpable splenomegaly

Absolute erythrocytosis Half of the patients have leukocytosis and/or thrombocytosis

Clonal genetic abnormalities in marrow cells

No causes of secondary erythrocytosis

Low serum EPO levels Palpable splenomegaly

Polycythemia Vera (PV). Clinical features

Polycythemia Vera (PV). Clinical features

Median age of onset 65 yo Most common cause of death is thrombosis cerebral, coronary or mesenteric

Headaches, visual problems, mental clouding, pruritus after bathing

Stroke, TIAs , Myocardial ischemia, paresthesias, digital pain, and gangrene

Pulmonary, hepatic and portal venous thrombosis

Hemorrhagic events, GI bleeding

Median age of onset 65 yo Most common cause of death is thrombosis cerebral, coronary or mesenteric

Headaches, visual problems, mental clouding, pruritus after bathing

Stroke, TIAs , Myocardial ischemia, paresthesias, digital pain, and gangrene

Pulmonary, hepatic and portal venous thrombosis

Hemorrhagic events, GI bleeding

Polycythemia Vera (PV).Labs

Polycythemia Vera (PV).Labs

P.exam : retinal - vein occlusion , cyanosis, splenomegaly

Microcytic cells Hypercellular marrow

P.exam : retinal - vein occlusion , cyanosis, splenomegaly

Microcytic cells Hypercellular marrow

Polycythemia Vera (PV).Treatment Polycythemia Vera (PV).Treatment

W/O treatment 50% mortality at 18 months of Dx

With therapy-chronic progressive disease

5-20% risk of Myelofibrosis/Myeloid leukemia over 20 years

Excellent long term survival/effective therapy

Goal of therapy: Hematocrit <45% in men Hematocrit <42% in women

W/O treatment 50% mortality at 18 months of Dx

With therapy-chronic progressive disease

5-20% risk of Myelofibrosis/Myeloid leukemia over 20 years

Excellent long term survival/effective therapy

Goal of therapy: Hematocrit <45% in men Hematocrit <42% in women

Polycythemia Vera (PV).treatment

Polycythemia Vera (PV).treatment

Intermittent phlebotomy Cytoreductive therapy/allopurinol if hyperuricemia

Hydroxyurea -low cytotoxic agent

Interferon alpha Anagrelide megakaryotoxic agent ASA or NSAIDS

Intermittent phlebotomy Cytoreductive therapy/allopurinol if hyperuricemia

Hydroxyurea -low cytotoxic agent

Interferon alpha Anagrelide megakaryotoxic agent ASA or NSAIDS

Essential Thrombocythemia


Increased Plts and WBCs Plt count >600,000 with normal RBC mass

Iron studies are normal Predominant proliferation in mature Megakariocytes

No “factor independent”colony growth

Increased Plts and WBCs Plt count >600,000 with normal RBC mass

Iron studies are normal Predominant proliferation in mature Megakariocytes

No “factor independent”colony growth

Essential Thrombocythemia. Clinical Features

Essential Thrombocythemia. Clinical Features

60-65yo, 10-25% younger than 40yo Headaches , dizziness, visual changes, and erythromelalgia(burning pain and erythema in the hands and feet)

TIAs, strokes, seizure, angina, MI may occur

Great long term survival rate

60-65yo, 10-25% younger than 40yo Headaches , dizziness, visual changes, and erythromelalgia(burning pain and erythema in the hands and feet)

TIAs, strokes, seizure, angina, MI may occur

Great long term survival rate



Low risk of leukemic transformation

High morbidity from hemorrhagic and thrombotic events

Aggressive management Cardio- vascular risk factors recommended

Therapy: ASA, 1rts line-Hydroxyurea, 2nd line-Anagrelide, interferon alpha

Low risk of leukemic transformation

High morbidity from hemorrhagic and thrombotic events

Aggressive management Cardio- vascular risk factors recommended

Therapy: ASA, 1rts line-Hydroxyurea, 2nd line-Anagrelide, interferon alpha

MyelofibrosisMyelofibrosis

Excessive marrow fibrosis leading to marrow failure

Dysplastic megakaryocytes producing increased levels of fibroblast growth factors

Abnormal proliferation and collagen deposition which displaces precursors cells to the periphery: extramedullary hematopoiesis

Excessive marrow fibrosis leading to marrow failure

Dysplastic megakaryocytes producing increased levels of fibroblast growth factors

Abnormal proliferation and collagen deposition which displaces precursors cells to the periphery: extramedullary hematopoiesis

Myelofibrosis Myelofibrosis

Early- asymptomatic, occasional low blood counts

Rare, chronic disease of the elderly

Median survival poor, 2-5 years Diagnosis :

Fibrosis in BM Normal RBC mass Lack of Philadelphia chromosome

Early- asymptomatic, occasional low blood counts

Rare, chronic disease of the elderly

Median survival poor, 2-5 years Diagnosis :

Fibrosis in BM Normal RBC mass Lack of Philadelphia chromosome

Myelofibrosis Myelofibrosis

Leukoerythroblastic changes in smear: Tear-drop cells Giant platelets Immature RBCS and WBCs

Leukoerythroblastic changes in smear: Tear-drop cells Giant platelets Immature RBCS and WBCs


Progressive fatigue and dypsnea

Early satiety and LUQ pain Massive hepatosplenomegaly With progressive BM failure, DIC may be present

Constitutional symptoms: Fevers, weight loss, night sweats

Progressive fatigue and dypsnea

Early satiety and LUQ pain Massive hepatosplenomegaly With progressive BM failure, DIC may be present

Constitutional symptoms: Fevers, weight loss, night sweats


Treatment, not shown to prolong survival:

Palliative transfusions EPO Hydroxyurea (to manage leukocytosis/thrombocytosis)

Splenectomy(extra medullary hematopoiesis)

Palliative splenic irradiation Allogeneic stem cell transplantation

Treatment, not shown to prolong survival:

Palliative transfusions EPO Hydroxyurea (to manage leukocytosis/thrombocytosis)

Splenectomy(extra medullary hematopoiesis)

Palliative splenic irradiation Allogeneic stem cell transplantation

Chronic Myeloid Leukemia CML


Overproduction myeloid cells Normal differentiation during early phases

Transform into more malignant disease: accelerated acute blast phase

Philadelphia chromosome: reciprocal translocation between the long arms of chromosomes 9 and 22 - producing the oncogene-fusion gene bcr/abl

Overproduction myeloid cells Normal differentiation during early phases

Transform into more malignant disease: accelerated acute blast phase

Philadelphia chromosome: reciprocal translocation between the long arms of chromosomes 9 and 22 - producing the oncogene-fusion gene bcr/abl



Median age at presentation 55 yo Hypermetabolic state signs

Chronic fatigue Night sweats Low grade fever

Abdominal fullness - splenomegaly Leukostasis(WBCs >500,000/mcl) - blurred vision, repiratory distress, or priapism

Median age at presentation 55 yo Hypermetabolic state signs

Chronic fatigue Night sweats Low grade fever

Abdominal fullness - splenomegaly Leukostasis(WBCs >500,000/mcl) - blurred vision, repiratory distress, or priapism



On P.Exam Enlarged spleen Sternal tenderness (marrow overexpansion)

Acceleration of disease associated to: High fever in the absence of infection

Bone pain splenomegaly

On P.Exam Enlarged spleen Sternal tenderness (marrow overexpansion)

Acceleration of disease associated to: High fever in the absence of infection

Bone pain splenomegaly



Laboratory findings: Elevated WBC counts - Hallmark (150,000/mcl)

Peripheral blood-left shifted Mature cells predominate Basophilia and Eosinophilia Blasts <5% Philadelphia chromosome present

Laboratory findings: Elevated WBC counts - Hallmark (150,000/mcl)

Peripheral blood-left shifted Mature cells predominate Basophilia and Eosinophilia Blasts <5% Philadelphia chromosome present

Chronic Myeloid Leukemia

Chronic Myeloid Leukemia

Bone Marrow changes: Initial - hypercellular / left shifted Myeloblasts comprise 5% marrow cells

Blast phase Blasts constitute >20% of the BM cells

Bone Marrow changes: Initial - hypercellular / left shifted Myeloblasts comprise 5% marrow cells

Blast phase Blasts constitute >20% of the BM cells

Chronic Myeloid Leukemia CMLChronic Myeloid Leukemia CML

Differential Diagnosis From Reactive leukocytosis

WBC <50,000/mcl Splenomegaly absent Philadelphia chromosome not present

From other myeloproliferative disorders. On CML you find: Hct is normal RBC morphology normal Nucleated RBCs rare or absent

Differential Diagnosis From Reactive leukocytosis

WBC <50,000/mcl Splenomegaly absent Philadelphia chromosome not present

From other myeloproliferative disorders. On CML you find: Hct is normal RBC morphology normal Nucleated RBCs rare or absent

CML-TreatmentCML-Treatment Chronic phase

Imatinib mesylate :inhibits the activity of the oncogene

400mg daily , oral

98% control of chronic phase Complete hematologic remission(3months)

Normal blood counts and resolution of splenomegaly

Cytogenetic response (6-12months) Major cytogenetic response <35%cont. Phil. Chromosome

Complete cytogenetic response - absence of Phil.Chromosome

Chronic phase Imatinib mesylate :inhibits the activity of the oncogene

400mg daily , oral

98% control of chronic phase Complete hematologic remission(3months)

Normal blood counts and resolution of splenomegaly

Cytogenetic response (6-12months) Major cytogenetic response <35%cont. Phil. Chromosome

Complete cytogenetic response - absence of Phil.Chromosome

CML-TreatmentCML-Treatment

Quantitative asesment Philadelphia Chromosome by Polymerase Chain Reaction (PCR)

Only curative therapy is allogeneic stem cell transplantation

Original therapy with Imatimib, if not optimum response-BM transplant is done

Quantitative asesment Philadelphia Chromosome by Polymerase Chain Reaction (PCR)

Only curative therapy is allogeneic stem cell transplantation

Original therapy with Imatimib, if not optimum response-BM transplant is done

CML-prognosisCML-prognosis

Past - 3 to 4years median survival

Now - Imatinib - more than 80% of patients alive and in remission at 4years

Past - 3 to 4years median survival

Now - Imatinib - more than 80% of patients alive and in remission at 4years

Chronic Lymphocytic Leukemias CLL


Malignant disorder of B-lymphocytes Most common leukemia in US More common in men Incidence increases with age 90% cases adults >50 yo Cause unknown Clonal proliferation of mature B cells

Malignant disorder of B-lymphocytes Most common leukemia in US More common in men Incidence increases with age 90% cases adults >50 yo Cause unknown Clonal proliferation of mature B cells

Chronic Lymphocytic Leukemia CLL

Chronic Lymphocytic Leukemia CLL

30-50% patients show cytogenetics abnormalities (trisomy 12) poor prognostic

Indolent course Cells are immuno-incompetent Immunosuppression, BM failure , and organ infiltration

Inadequate antibody production Tissue damage by direct organ infiltration

30-50% patients show cytogenetics abnormalities (trisomy 12) poor prognostic

Indolent course Cells are immuno-incompetent Immunosuppression, BM failure , and organ infiltration

Inadequate antibody production Tissue damage by direct organ infiltration



Clinical symptoms Lymphadenopathy Fatigue Enlarged liver or spleen May complicate with autoimmune hemolytic anemia, or thrombocytopenia

Isolated lymph node transforms into large cell lymphoma(Richter’s syndrome)

Clinical symptoms Lymphadenopathy Fatigue Enlarged liver or spleen May complicate with autoimmune hemolytic anemia, or thrombocytopenia

Isolated lymph node transforms into large cell lymphoma(Richter’s syndrome)



Laboratory findings Hallmark - isolated lymphocytosis >20k or several hundred thousand

Main cell - small mature looking lymphocytes

Hct and Plt count normal at presentation

BM infiltration by small mature looking lymphocytes

hypogammaglobulinemia

Laboratory findings Hallmark - isolated lymphocytosis >20k or several hundred thousand

Main cell - small mature looking lymphocytes

Hct and Plt count normal at presentation

BM infiltration by small mature looking lymphocytes

hypogammaglobulinemia



Classification - Rai system Stage 0 - lymphocytosis only Stage I - lymphocytosis + lymph-adenopathy

Stage II- organomegaly Stage III-anemia Stage IV- thrombocytopenia

Classification - Rai system Stage 0 - lymphocytosis only Stage I - lymphocytosis + lymph-adenopathy

Stage II- organomegaly Stage III-anemia Stage IV- thrombocytopenia



Indications for therapy include: Fatigue, lymphadenopathy, anemia or thrombocytopenia

Combination therapy with fludarabine + rituxan given for 6 months

Chlorambucil for the elderly Alemtuzumab- monoc.ab for refractory cases

Indications for therapy include: Fatigue, lymphadenopathy, anemia or thrombocytopenia

Combination therapy with fludarabine + rituxan given for 6 months

Chlorambucil for the elderly Alemtuzumab- monoc.ab for refractory cases

Acute LeukemiasAcute Leukemias

Classification by: Cell lineage Morphology Cytogenetics Cell surface and Cytoplasmic markers

Molecular studies

Classification by: Cell lineage Morphology Cytogenetics Cell surface and Cytoplasmic markers

Molecular studies


Classification by cell lineage: Acute Myeloblastic Leukemia (AML)

90% adult Leukemias Acute Lymphoblastic Leukemia (ALL)

90% of childhood Leukemias

Classification by cell lineage: Acute Myeloblastic Leukemia (AML)

90% adult Leukemias Acute Lymphoblastic Leukemia (ALL)

90% of childhood Leukemias


Unregulated proliferation of immature cells that are incapable of further differentiation (blasts)>20% in BM

Not clear cause Risk factors: radiations, toxins, chemotherapeutic agents

Unregulated proliferation of immature cells that are incapable of further differentiation (blasts)>20% in BM

Not clear cause Risk factors: radiations, toxins, chemotherapeutic agents


Results in marrow replacement Hematopoietic failure Organ infiltration(GI, Skin, Meninges)

AML - affects adults – 60 yo ALL – affects children 3-7 yo

Results in marrow replacement Hematopoietic failure Organ infiltration(GI, Skin, Meninges)

AML - affects adults – 60 yo ALL – affects children 3-7 yo

Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia (ALL)

Affects immature lymphoblasts FAB class. L1, L2, L3(cell morphology)

More recent, WHO classification. Precursor B ALL Precursor T ALL Based on cell surface Ags present on these cells during maturation

Affects immature lymphoblasts FAB class. L1, L2, L3(cell morphology)

More recent, WHO classification. Precursor B ALL Precursor T ALL Based on cell surface Ags present on these cells during maturation

Acute Leukemias Acute Leukemias

Cure rates 80% in children, 20-40% in adults

Patient not feeling well for days or weeks

Anemia, infection, and bleeding from peripheral cytopenias

Bone pain f.marrow infiltration

Cure rates 80% in children, 20-40% in adults

Patient not feeling well for days or weeks

Anemia, infection, and bleeding from peripheral cytopenias

Bone pain f.marrow infiltration


Risk of infection increases with neutrophils counts below 500/mcl

Common pathogens: gram neg.bact. and Fungi

Cellulitis, pneumonia, and perirectal infections

Gum hyperthrophy and bone and joint pain is possible

Risk of infection increases with neutrophils counts below 500/mcl

Common pathogens: gram neg.bact. and Fungi

Cellulitis, pneumonia, and perirectal infections

Gum hyperthrophy and bone and joint pain is possible

Acute Leukemia PEAcute Leukemia PE

Pallor, purpura or petechiae Stomatitis , gum hyperthrophy Lymphadenopathy, hepato-splenomegaly

Bone tenderness sternum ,tibia, and femur

Pallor, purpura or petechiae Stomatitis , gum hyperthrophy Lymphadenopathy, hepato-splenomegaly

Bone tenderness sternum ,tibia, and femur

Laboratory Findings Laboratory Findings

Hallmark-pancytopenias with circulating blasts

BM- hypercellular with more than 20% blasts (required for Dx)

Hyperuricemia may be present If DIC present-decreased fibrinogen level, Pt is prolonged and FDP present

Hallmark-pancytopenias with circulating blasts

BM- hypercellular with more than 20% blasts (required for Dx)

Hyperuricemia may be present If DIC present-decreased fibrinogen level, Pt is prolonged and FDP present

Laboratory FindingsLaboratory Findings

Patients with ALL may have a mediastinal mass present on chest Xray

Auer rods-eosinophilic needle like in the Cytoplasm-pathognomonic for AML

Histochemical stains- Myeloid lineage - Myeloperoxidase Monocytic lineage – butyrate esterase

Patients with ALL may have a mediastinal mass present on chest Xray

Auer rods-eosinophilic needle like in the Cytoplasm-pathognomonic for AML

Histochemical stains- Myeloid lineage - Myeloperoxidase Monocytic lineage – butyrate esterase

ALLALL

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ALL. considered if no morphological or histochemical stains demonstrate Myeloid precursors

Surface markers for lymphoid precursors are demonstrate by flow cytometry –TdT terminal present in 95% of ALL

ALL. considered if no morphological or histochemical stains demonstrate Myeloid precursors

Surface markers for lymphoid precursors are demonstrate by flow cytometry –TdT terminal present in 95% of ALL

Monoclonal antibodies to Lymphocytes antigens: Primitive B lymphocytes-CD19/CD10

Primitive T cell-CD2/CD5/CD7 Cytogenetics studies are used to determine prognosis

Monoclonal antibodies to Lymphocytes antigens: Primitive B lymphocytes-CD19/CD10

Primitive T cell-CD2/CD5/CD7 Cytogenetics studies are used to determine prognosis


Acute Leukemias Treatment


ALL Lengthy /multiple chemotherapy given over a period of 2-3 years

Induction chemotherapy: reduce blasts to undetectable levels, and restores normal hematopoiesis Vincristine Corticosteroids L-asparaginase Cytabarine

ALL Lengthy /multiple chemotherapy given over a period of 2-3 years

Induction chemotherapy: reduce blasts to undetectable levels, and restores normal hematopoiesis Vincristine Corticosteroids L-asparaginase Cytabarine



Consolidation therapy: continuing chemotherapy same agents to induce elimination of further leukemic cells

Intensification therapy: to treat cells resistant to the induction regimen

Maintenance therapy: low-dose intermittent chemotherapy to prevent relapse

Consolidation therapy: continuing chemotherapy same agents to induce elimination of further leukemic cells

Intensification therapy: to treat cells resistant to the induction regimen

Maintenance therapy: low-dose intermittent chemotherapy to prevent relapse



Remission: presence of less than 5 % blasts in the BM with restoration of normal peripheral blood counts

Intratechal chemotherapy and brain irradiation to destroy cells in the CNS and testes (leukemia Sanctuaries)

The worse the prognosis the early the transplant of BM should be offered

Remission: presence of less than 5 % blasts in the BM with restoration of normal peripheral blood counts

Intratechal chemotherapy and brain irradiation to destroy cells in the CNS and testes (leukemia Sanctuaries)

The worse the prognosis the early the transplant of BM should be offered

Acute Myeloid LeukemiaAcute Myeloid Leukemia

See Classification for AML in the Book

Leukostasis / hyperleukocytosis syndrome High levels of circulating blasts

Diffuse pulmonary infiltrates Acute respiratory distress

See Classification for AML in the Book

Leukostasis / hyperleukocytosis syndrome High levels of circulating blasts

Diffuse pulmonary infiltrates Acute respiratory distress

Acute Myeloid Leukemia AML


Blast cells may also injure vasculature causing CNS bleeding

Hyperkalemia , acidosis and hyperuricemia caused by increased cell breakdown can precipitate renal failure

Leukophoresis , Hydroxyurea, and hydration to avoid more damage

Blast cells may also injure vasculature causing CNS bleeding

Hyperkalemia , acidosis and hyperuricemia caused by increased cell breakdown can precipitate renal failure

Leukophoresis , Hydroxyurea, and hydration to avoid more damage



Stem cell transplant only hope for cure in some patients with AML and poor prognosis, or after relapse

Stem cell transplant only hope for cure in some patients with AML and poor prognosis, or after relapse

Lymphocytes Disorders Lymphocytes Disorders

Neoplasia of Lymphoid origin Non Hodgkin’s Lymphoma Hodgkin’s Lymphoma Lymphoid Leukemia Plasma cells Dyscrasias

Neoplasia of Lymphoid origin Non Hodgkin’s Lymphoma Hodgkin’s Lymphoma Lymphoid Leukemia Plasma cells Dyscrasias

Lymphadenopathy Lymphadenopathy

Painless enlargement of the lymph nodes is the most common presentation of lymphoid malignancy in adults

Cervical lymphadenopathy: URI IM Bacterial pharyngitis Other viral syndromes

Painless enlargement of the lymph nodes is the most common presentation of lymphoid malignancy in adults

Cervical lymphadenopathy: URI IM Bacterial pharyngitis Other viral syndromes

LymphadenopathyLymphadenopathy

Unilateral axillary, inguinal, or femoral adenopathy may be caused by local skin infections involving the affected area

Generalized lymphadenopathy caused by systemic infections such as HIV, drug reactions, autoimmune Ds, lymphoma, or others

Unilateral axillary, inguinal, or femoral adenopathy may be caused by local skin infections involving the affected area

Generalized lymphadenopathy caused by systemic infections such as HIV, drug reactions, autoimmune Ds, lymphoma, or others

LymphadenopathyLymphadenopathy

Excisional lymph node biopsy is done if no apparent cause

Histological examination and immunophenotyping for classification

Excisional lymph node biopsy is done if no apparent cause

Histological examination and immunophenotyping for classification

Non Hodgkin’s LymphomaNon Hodgkin’s Lymphoma

Heterogeneous group of cancers of the lymphocytes

From indolent course to rapidly progressing

Cause not known Frequently associated with chromosomal translocations

Heterogeneous group of cancers of the lymphocytes

From indolent course to rapidly progressing

Cause not known Frequently associated with chromosomal translocations



Different classifications through the years

Most updated one REAL/WHO REAL: Revised European-American Lymphoma Classification updated by WHO: World Health Organization in 2001

Different classifications through the years

Most updated one REAL/WHO REAL: Revised European-American Lymphoma Classification updated by WHO: World Health Organization in 2001


Most common types in the US: Follicular lymphomas Chronic Lymphocytic Leukemia(CLL) or small lymphocytic lymphoma

Mantel cell lymphomas Diffuse large B-cell Lymphomas

Most common types in the US: Follicular lymphomas Chronic Lymphocytic Leukemia(CLL) or small lymphocytic lymphoma

Mantel cell lymphomas Diffuse large B-cell Lymphomas


Associated with oncogenic viruses:

EBV-AIDS related lymphomas EBV-related to the Burkitt’s lymphoma that is endemic in Africa

HTLV-1 causally linked to T-cell leukemia endemic in Japan and the Caribbean

Associated with oncogenic viruses:

EBV-AIDS related lymphomas EBV-related to the Burkitt’s lymphoma that is endemic in Africa

HTLV-1 causally linked to T-cell leukemia endemic in Japan and the Caribbean


Extra nodal site involvement in the GI , BM, liver, and Waldeyer’s ring or any part of the body

More aggressive types have more extra nodal or diffuse involvement including CNS (Burkitt’s and Lymphoblastics)

Extra nodal site involvement in the GI , BM, liver, and Waldeyer’s ring or any part of the body

More aggressive types have more extra nodal or diffuse involvement including CNS (Burkitt’s and Lymphoblastics)


After diagnosis of Lymphoma Staging: determines the extent of involvement , prognosis, and may influence the choice of therapy

Modified Ann Arbor staging classification is used for both non H. and Hodgkin’s Lymphoma

After diagnosis of Lymphoma Staging: determines the extent of involvement , prognosis, and may influence the choice of therapy

Modified Ann Arbor staging classification is used for both non H. and Hodgkin’s Lymphoma

Stage l: single lymph node region or structure, or extra lymphatic site

Stage ll: two or more lymph node regions on the same side of the Diaphragm or contiguous extra lymphatic site and lymph node region

Stage lll: involvement of lymph nodes regions on both sides of the Diaphragm , accompanied by extra lymphatic site or spleen or both

Stage lV diffuse or disseminated involvement of one or more extra lymphatic organs with or without associated lymph node involvement

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Stage l: single lymph node region or structure, or extra lymphatic site

Stage ll: two or more lymph node regions on the same side of the Diaphragm or contiguous extra lymphatic site and lymph node region

Stage lll: involvement of lymph nodes regions on both sides of the Diaphragm , accompanied by extra lymphatic site or spleen or both

Stage lV diffuse or disseminated involvement of one or more extra lymphatic organs with or without associated lymph node involvement

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Staging evaluationStaging evaluation

History-constitutional symptoms (fever, nights sweats, and weight loss-B symptoms)

Complete PE – Lymph Nodes size and distribution

Blood work CT scan ABD.CHEST.PELVIS BM aspirate and Biopsy PET scan Lumbar puncture

History-constitutional symptoms (fever, nights sweats, and weight loss-B symptoms)

Complete PE – Lymph Nodes size and distribution

Blood work CT scan ABD.CHEST.PELVIS BM aspirate and Biopsy PET scan Lumbar puncture


Low grade/indolent includes : Follicular lymphomas Small lymphocytic lymphomas(CLL)

Are mature clonal B cell neoplasm Advanced stage or disseminated at presentation (80-90%)

Non curable, and long natural Hx, watch and wait strategy

Advanced stage – systemic chemotherapy

Low grade/indolent includes : Follicular lymphomas Small lymphocytic lymphomas(CLL)

Are mature clonal B cell neoplasm Advanced stage or disseminated at presentation (80-90%)

Non curable, and long natural Hx, watch and wait strategy

Advanced stage – systemic chemotherapy


Patients with diffuse aggressive lymphoma are treated immediately because these are potentially curable

Multidrug chemotherapy including anthracycline

CHOP: most common regimen, includes cyclophosphamide, doxorubicin, vincristine, and prednisone

30-40% cure rate

Patients with diffuse aggressive lymphoma are treated immediately because these are potentially curable

Multidrug chemotherapy including anthracycline

CHOP: most common regimen, includes cyclophosphamide, doxorubicin, vincristine, and prednisone

30-40% cure rate


Burkitt’s Lymphoma: High grade B cell Lymphoma, rare in adults ,endemic in children in Africa (EBV), curable

Involve BM , and CNS Urgent inpatient treatment, highly aggressive/rapid growth

Frequent abdominal pain and fullness /abdomen predilection

Tumor Lysis Syndrome common

Burkitt’s Lymphoma: High grade B cell Lymphoma, rare in adults ,endemic in children in Africa (EBV), curable

Involve BM , and CNS Urgent inpatient treatment, highly aggressive/rapid growth

Frequent abdominal pain and fullness /abdomen predilection

Tumor Lysis Syndrome common


Lymphoblastic lymphoma (ALL) T-cell lymphoma

+ tdt (terminal deoxynucleotide tranferase)

Young male adults Involves mediastinum and BM

Lymphoblastic lymphoma (ALL) T-cell lymphoma

+ tdt (terminal deoxynucleotide tranferase)

Young male adults Involves mediastinum and BM

Both require intensive treatment with multiple therapy

intrathecal therapy to prevent relapse Prophylaxis for “tumor lysis syndrome” with hydration, alkalinization of the urine and allopurinol

BM autologous transplant used MALT(mucosal associated lymp.tumors) of the stomach treated with antibiotics-H.pilory

Both require intensive treatment with multiple therapy

intrathecal therapy to prevent relapse Prophylaxis for “tumor lysis syndrome” with hydration, alkalinization of the urine and allopurinol

BM autologous transplant used MALT(mucosal associated lymp.tumors) of the stomach treated with antibiotics-H.pilory


Prognosis Prognosis

Adverse prognosis factors: Age over 60 yo Elevated serum LDH Stage lll or IV Poor performance state Durable complete response 80%-no risk patients

Early treatment with high dose therapy and autologous stem cell transplant improves the outcome

Adverse prognosis factors: Age over 60 yo Elevated serum LDH Stage lll or IV Poor performance state Durable complete response 80%-no risk patients

Early treatment with high dose therapy and autologous stem cell transplant improves the outcome

Hodgkin’s diseaseHodgkin’s disease

Painless lymphadenopathy Constitutional symptoms may or may not be present

Diagnosis by lymph node biopsy Reed-sternberg(RS) cells present in lymphoid tissue involved

Painless lymphadenopathy Constitutional symptoms may or may not be present

Diagnosis by lymph node biopsy Reed-sternberg(RS) cells present in lymphoid tissue involved

Hodgkin’s diseaseHodgkin’s disease Reed-Sternberg cell: bi-nucleated cell with nucleoli - owl’s eyes, B cell in nature, present in only half the HD patients

Reed-Sternberg cell: bi-nucleated cell with nucleoli - owl’s eyes, B cell in nature, present in only half the HD patients


Bimodal age distribution 20yo and >50yo

Presents as painless mass(neck) and spreads to contiguous lymph nodes

Some have constitutional symptoms only, and generalized pruritus

Pain in in lymph node after alcohol ingestion

Late in course - Vascular invasion and hematogenous spread

Bimodal age distribution 20yo and >50yo

Presents as painless mass(neck) and spreads to contiguous lymph nodes

Some have constitutional symptoms only, and generalized pruritus

Pain in in lymph node after alcohol ingestion

Late in course - Vascular invasion and hematogenous spread

Hodgkin’s diseaseHodgkin’s disease Four Pathological Variants:

Nodular Sclerosing(80%) Young adults/mediastinum/above Diaph

Mixed cellularity (15%) Any age group/subdiaphragmatic common

Lymphocyte depleted (1%) Older adults/HIV patients

Lymphocyte predominant (5%) Peripheral nodes involvement Polylobated nuclei RS cells(popcorn cells)

Four Pathological Variants: Nodular Sclerosing(80%)

Young adults/mediastinum/above Diaph Mixed cellularity (15%)

Any age group/subdiaphragmatic common Lymphocyte depleted (1%)

Older adults/HIV patients Lymphocyte predominant (5%)

Peripheral nodes involvement Polylobated nuclei RS cells(popcorn cells)

HL Mixed CellularityHL Mixed Cellularity


Advanced disease: BM failure and malaise , cachexia , infections

Staging the same as for NHL with the addition of A or B for the absence or presence of B symptoms respectively

Advanced disease: BM failure and malaise , cachexia , infections

Staging the same as for NHL with the addition of A or B for the absence or presence of B symptoms respectively

Staging WorkupStaging Workup Similar to NHL Thorough H & P Blood work including ESR Chest Xray CT chest, abdomen, pelvis BM aspirate /Biopsy PETscan/gallium scan Bone scan, spinal magnetic resonance if needed

Similar to NHL Thorough H & P Blood work including ESR Chest Xray CT chest, abdomen, pelvis BM aspirate /Biopsy PETscan/gallium scan Bone scan, spinal magnetic resonance if needed

HL TreatmentHL Treatment

Radiation therapy- initial for low risk IA and IIA disease

Trial limited chemotherapy for some patients-

IIIB, IV - combination chemotherapy Adriamycin(doxorubicin) Bleomycin Vincristine dacarbazine

Radiation therapy- initial for low risk IA and IIA disease

Trial limited chemotherapy for some patients-

IIIB, IV - combination chemotherapy Adriamycin(doxorubicin) Bleomycin Vincristine dacarbazine

HL prognosisHL prognosis

IA, IIA- excellent >80% surv.rate after 10 years

IIIB, IV- 50-60% at 5 years Better prognosis - the Lymphocyte Predominant subtype

Treatment after relapse is high dose chemotherapy and autologous stem cell transplant

IA, IIA- excellent >80% surv.rate after 10 years

IIIB, IV- 50-60% at 5 years Better prognosis - the Lymphocyte Predominant subtype

Treatment after relapse is high dose chemotherapy and autologous stem cell transplant

Plasma cells DisordersPlasma cells Disorders B cells neoplasm with production and secretion of monoclonal(M) immunoglobulin or part of an immunoglobulin molecule

Mature plasma cells which produce large amount of immunoglobulins

Protein can be detected in serum or urine by Protein Electrophoresis test

B cells neoplasm with production and secretion of monoclonal(M) immunoglobulin or part of an immunoglobulin molecule

Mature plasma cells which produce large amount of immunoglobulins

Protein can be detected in serum or urine by Protein Electrophoresis test

Plasma cells DisordersPlasma cells Disorders

Clinically characterized by: Systemic effect of the M protein direct effect of bone and BM infiltration by the M protein

Classification by the immunoglobulin produced(G,A,D,M,E,) or component produced(heavy or light chain)

Clinically characterized by: Systemic effect of the M protein direct effect of bone and BM infiltration by the M protein

Classification by the immunoglobulin produced(G,A,D,M,E,) or component produced(heavy or light chain)

Plasma cells DisordersPlasma cells Disorders M proteins found also in benign and malignant conditions

Autoreactive and infectious disorders

MGUS Low level M protein on serum No associated abnormalities More common than Multiple Myeloma Considered pre-malignant Monitor patient annual PE

M proteins found also in benign and malignant conditions

Autoreactive and infectious disorders

MGUS Low level M protein on serum No associated abnormalities More common than Multiple Myeloma Considered pre-malignant Monitor patient annual PE

Plasma cells DisordersPlasma cells Disorders Multiple Myeloma (MM)

Neoplastic infiltration of bone and BM

M Immunoglobulin or light chains in the serum or urine

Dx >30% plasma cells in BM Serum M protein other than IgM

IgG >3g/dl IgA >2g/dl

Urine M protein 1g/24 hrs

Multiple Myeloma (MM) Neoplastic infiltration of bone and BM

M Immunoglobulin or light chains in the serum or urine

Dx >30% plasma cells in BM Serum M protein other than IgM

IgG >3g/dl IgA >2g/dl

Urine M protein 1g/24 hrs


20% of patients lack the M protein in serum but show light chains protein in urine

Diagnosis made in this cases by presence of hypogammaglobulinemia, lytic bone lesions, or plasmacytoma

20% of patients lack the M protein in serum but show light chains protein in urine

Diagnosis made in this cases by presence of hypogammaglobulinemia, lytic bone lesions, or plasmacytoma

Plasma cells DisordersPlasma cells Disorders Clinical Manifestations MM Results from

Bone or BM infiltration of Plasma Cells

Systemic effects of the M protein And humoral immune deficiency

Clinical Manifestations MM Results from

Bone or BM infiltration of Plasma Cells

Systemic effects of the M protein And humoral immune deficiency

Plasma cells Disorders MM

Plasma cells Disorders MM Bone Pain- Bone Xray-osteolytic -

punched out lesions- low back and ribs

Osteopenia-pathologic fractures-spinal cord compression

Hypercalcemia - bony involvement Anemia - BM infiltration Decreased WBC and Plts less common Increased infections Renal insufficiency - hypercalcemia/uricemia

Bone Pain- Bone Xray-osteolytic -punched out lesions- low back and ribs

Osteopenia-pathologic fractures-spinal cord compression

Hypercalcemia - bony involvement Anemia - BM infiltration Decreased WBC and Plts less common Increased infections Renal insufficiency - hypercalcemia/uricemia


Hyperviscocity ,cryoglobulinemia- vertigo, nausea, visual disturbances, alter mental status

Clotting abnormalities Enlarged tongue - amyloidosis

Hyperviscocity ,cryoglobulinemia- vertigo, nausea, visual disturbances, alter mental status

Clotting abnormalities Enlarged tongue - amyloidosis


Lab Findings RBC morphology WNL - Rouleau formation

Hallmark - paraprotein in SPEP Immunofixation to determine if monoclonal

BM plasma cells 20-100% abnormal

Lab Findings RBC morphology WNL - Rouleau formation

Hallmark - paraprotein in SPEP Immunofixation to determine if monoclonal

BM plasma cells 20-100% abnormal



Diff Diagnosis MGUS Waldestrom’s macroglobulinemia Reactive polyclonal hypergammaglobulinemia

Lymphomas Primary amyloidosis

Diff Diagnosis MGUS Waldestrom’s macroglobulinemia Reactive polyclonal hypergammaglobulinemia

Lymphomas Primary amyloidosis



Treatment Thalidomide + dexamethasone Stem cell transplant Treat hypercalcemia Biphosphonates

Treatment Thalidomide + dexamethasone Stem cell transplant Treat hypercalcemia Biphosphonates

Waldestrom’s Macroglobulinemia


Hybrid cell between B lymphocyte and plasma cell

Secrete IgM paraprotein Symptoms related to the macroglobulin Insidious course in the elderly Hyperviscocity in serum- GI bleeding Lethargy , stupor , or comma Peripheral neuropathy

Hybrid cell between B lymphocyte and plasma cell

Secrete IgM paraprotein Symptoms related to the macroglobulin Insidious course in the elderly Hyperviscocity in serum- GI bleeding Lethargy , stupor , or comma Peripheral neuropathy



PE Retinal vein engorgement Lymphadenopathy Hepatosplenomegaly Purpura

PE Retinal vein engorgement Lymphadenopathy Hepatosplenomegaly Purpura



Laboratory Findings Anemia- expansion of plasma (protein)

Rouleau formation Other blood counts normal BM infiltrated by plasmacytic lymphocytes

Hallmark- IgM spike on SPEP No renal failure No bone lesions

Laboratory Findings Anemia- expansion of plasma (protein)

Rouleau formation Other blood counts normal BM infiltrated by plasmacytic lymphocytes

Hallmark- IgM spike on SPEP No renal failure No bone lesions



Treatment Emergency plasmapheresis - hyperviscocity

Fludarabine and Rituxan Autologous cell transplant

Treatment Emergency plasmapheresis - hyperviscocity

Fludarabine and Rituxan Autologous cell transplant

WBC disordersWBC disorders

Leukocytosis : non specific term, denotes increased in either neutrophils or lymphocytes

Neutrophilia: increase in netrophils

Leukemoid reaction: Extreme elevation of WBCs >50,000/mcl and early myeloid precursors

Leukocytosis : non specific term, denotes increased in either neutrophils or lymphocytes

Neutrophilia: increase in netrophils

Leukemoid reaction: Extreme elevation of WBCs >50,000/mcl and early myeloid precursors


Leukemoid reaction: Associated with inflammatory reactions and infections

Leukopenia: decrease in lymphocytes or neutrophils

Neutropenia : neutrophil count <1500/mcl

Leukemoid reaction: Associated with inflammatory reactions and infections

Leukopenia: decrease in lymphocytes or neutrophils

Neutropenia : neutrophil count <1500/mcl

WBC disordersWBC disorders Neutropenia

Decreased production (congenital/acquired)

Increased sequestration (splenomegaly)

Peripheral destruction (overwhelming infections, drug related, Collagen vascular disease

Neutropenia Decreased production (congenital/acquired)

Increased sequestration (splenomegaly)

Peripheral destruction (overwhelming infections, drug related, Collagen vascular disease


Cyclic neutropenia: asymptomatic patients, evaluate with serial CBCs Neutrophil count varies by ethnic group, lower in African-Americans

Relative benign condition If neutrophil count is very low can develop infections

Cyclic neutropenia: asymptomatic patients, evaluate with serial CBCs Neutrophil count varies by ethnic group, lower in African-Americans

Relative benign condition If neutrophil count is very low can develop infections


Congenital Agranulocytosis (Kostmann’s syndrome) Profound neutropenia Infections perinatal period Associate with development of acute leukemias

Better prognosis with cytokines therapy

Congenital Agranulocytosis (Kostmann’s syndrome) Profound neutropenia Infections perinatal period Associate with development of acute leukemias

Better prognosis with cytokines therapy


Post viral neutropenia Common in children Increased neutrophil consumption and viral suppression of BM

When associated to overwhelming sepsis-poor prognosis

Post viral neutropenia Common in children Increased neutrophil consumption and viral suppression of BM

When associated to overwhelming sepsis-poor prognosis


Drug induced Neutropenia Dose dependent or idiosyncratic reaction

Chemotherapy, Bactrin, Chloramphenicol

Most respond to discontinuation of the drug and G-CSF therapy

Drug induced Neutropenia Dose dependent or idiosyncratic reaction

Chemotherapy, Bactrin, Chloramphenicol

Most respond to discontinuation of the drug and G-CSF therapy


Autoimmune neutropenia Associated to Systemic autoimmune disorders

SLE, RA Not usually severe, indicator of disease activity

Autoimmune neutropenia Associated to Systemic autoimmune disorders

SLE, RA Not usually severe, indicator of disease activity

Neutropenia. Laboratory Eval.

Neutropenia. Laboratory Eval.

Serologic studies to rule out CVD

BM examination indicated early – frequently diagnostic

Most often reflects hematological conditions

Serologic studies to rule out CVD

BM examination indicated early – frequently diagnostic

Most often reflects hematological conditions

Neutropenia managementNeutropenia management 1000-1500/mcl no significant impairment, no treatment needed, find the cause and treat condition as needed

500-1000/mcl alert patient to increase risk of infection

<500/mcl significant risk of infection, should notify MD at any signs of infections-fever, aggressive antibiotic management

Patients with immune mediated neutropenia are managed with steroids and IVIG

1000-1500/mcl no significant impairment, no treatment needed, find the cause and treat condition as needed

500-1000/mcl alert patient to increase risk of infection

<500/mcl significant risk of infection, should notify MD at any signs of infections-fever, aggressive antibiotic management

Patients with immune mediated neutropenia are managed with steroids and IVIG

the the endend

the the endend

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Hematology Rivas2008 Lecture4&5

Health & Medicine