medicine2 - myeloproliferative, lymphoproliferative workshop

Section of Hematology & Oncology

Department of Medicine

Section of Hematology & Oncology

Department of Medicine

Myeloproliferative and Myeloproliferative and Lymphoproliferative DisordersLymphoproliferative Disorders

Myeloproliferative and Myeloproliferative and Lymphoproliferative DisordersLymphoproliferative Disorders

PNHPNHPNHPNH

CMMLCMMLCMMLCMML

MYELODYSPLASTIC MYELODYSPLASTIC SYNDROMESSYNDROMES

MYELODYSPLASTIC MYELODYSPLASTIC SYNDROMESSYNDROMES

RARSRARSRARSRARSRARARARA

AMLAML

RAEB, TRAEB, TRAEB, TRAEB, T

CMLCML

MYELOPROLIFERATIVE MYELOPROLIFERATIVE SYNDROMESSYNDROMES

MYELOPROLIFERATIVE MYELOPROLIFERATIVE SYNDROMESSYNDROMES

MMMMMM

LEUKEMIASLEUKEMIASLEUKEMIASLEUKEMIASCLL

ALL

P.V.P.V.P.V.P.V. E.T.E.T.E.T.E.T.

Clonal Bone Marrow DisordersClonal Bone Marrow DisordersClonal Bone Marrow DisordersClonal Bone Marrow Disorders

Kouides PA and Bennett JM. Kouides PA and Bennett JM. Sem Hematol,Sem Hematol, April 1996 April 1996Kouides PA and Bennett JM. Kouides PA and Bennett JM. Sem Hematol,Sem Hematol, April 1996 April 1996

Case 2-01-01Case 2-01-01Case 2-01-01Case 2-01-01 46 year old Filipino female profuse menstrual flow for the past few months on and off fever, easy bruisability, shortness of breath on exertion for the

past 3 weeks no headache, bone pain, nausea, vomiting, melena, hematochezia,

dysuria, nor hematuria denies any exposure to insecticides or other chemicals FH: diabetes mellitus Physical examination: BP: 100/70, pulse rate of 100/min, regular and

full; RR of 24/min pale, not jaundiced, no palpable cervical lymphadenopathy Cardiovascular and pulmonary examinations are normal Liver and spleen are not palpable Neurologic and musculoskeletal examinations are unremarkable

46 year old Filipino female profuse menstrual flow for the past few months on and off fever, easy bruisability, shortness of breath on exertion for the

past 3 weeks no headache, bone pain, nausea, vomiting, melena, hematochezia,

dysuria, nor hematuria denies any exposure to insecticides or other chemicals FH: diabetes mellitus Physical examination: BP: 100/70, pulse rate of 100/min, regular and

full; RR of 24/min pale, not jaundiced, no palpable cervical lymphadenopathy Cardiovascular and pulmonary examinations are normal Liver and spleen are not palpable Neurologic and musculoskeletal examinations are unremarkable

Case 2-01-01Case 2-01-01Case 2-01-01Case 2-01-01

CBC : hgb : 7.2wbc of 45,000 with blasts of 55%, platelets: 65,000.

CBC : hgb : 7.2wbc of 45,000 with blasts of 55%, platelets: 65,000.


1. What are blast cells? Describe them.

2. What laboratory examinations should be requested? Why?

3. What is/are your clinical impression(s)?

4. What is the appropriate management for this patient?

1. What are blast cells? Describe them.

2. What laboratory examinations should be requested? Why?

3. What is/are your clinical impression(s)?

4. What is the appropriate management for this patient?

Blast cellsBlast cellsBlast cellsBlast cells

Immature cells characterized morphologically as mononuclear cells with large nuclei relative to the cytoplasm, containing one or more nucleoli

May be of lymphoid or myeloid origin

Immature cells characterized morphologically as mononuclear cells with large nuclei relative to the cytoplasm, containing one or more nucleoli

May be of lymphoid or myeloid origin

Back to Questions

ExaminationsExaminationsExaminationsExaminations

Peripheral smear Bone marrow examination:

Aspirate Light microscopic studies Flow cytometry Cytogenetics

Biopsy

Blood chemistries: LFT, Renal function, BUA Others as indicated by clinical situation

Peripheral smear Bone marrow examination:

Aspirate Light microscopic studies Flow cytometry Cytogenetics

Biopsy

Blood chemistries: LFT, Renal function, BUA Others as indicated by clinical situation

AML, peripheral bloodAML, peripheral bloodAML, peripheral bloodAML, peripheral blood

Blast cells

Myelomonocytic leukemia

Acute promyelocytic leukemia

Acute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous LeukemiaAcute Myelogenous Leukemia

Undifferentiated

Myelomonocytic Monoblastic, bone marrow biopsy

Acute ErythroleukemiaAcute ErythroleukemiaAcute ErythroleukemiaAcute Erythroleukemia

Peripheral blood Bone marrow

ALL, microscopy & cytochemistryALL, microscopy & cytochemistryALL, microscopy & cytochemistryALL, microscopy & cytochemistry

Lymphoblasts, peripheral blood

PAS stain: lymphoblasts positive

Myeloperoxidase stain: lymphoblasts are negative

Alpha naphthyl esterase stain: lymphoblasts are negative

Immunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLCD GrpCD Grp AntibodiesAntibodies ReactivityReactivity

CFU-GEMM to promyelo-cyte and mature mono-cytes

CFU-GEMM to promyelo-cyte and mature mono-cytes

CD33CD33 MY9, LeuM9, L4F3MY9, LeuM9, L4F3

CFU-GM to mature granulo-cytes and monocytesCFU-GM to mature granulo-cytes and monocytes

CD13CD13 MY7, LeuM7MY7, LeuM7

MonocytesMonocytesCD14CD14 MY4, LeuM3, MO2MY4, LeuM3, MO2

CD15CD15 LeuM1, MY1LeuM1, MY1 Promyelocytes to granulo-cytes, monocytesPromyelocytes to granulo-cytes, monocytes

Immunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLImmunophenotyping: AMLCD GrpCD Grp AntibodiesAntibodies ReactivityReactivity

Progenitor cells, B- lymphocytes, monocytes, activated T-cells

Progenitor cells, B- lymphocytes, monocytes, activated T-cells

CD34CD34 MY10, HPCA-1, HLA-DR, Ia

MY10, HPCA-1, HLA-DR, Ia

Platelets and megakaryocytesPlatelets and megakaryocytes

CD41CD41 GPIIbIIIa, PL-273GPIIbIIIa, PL-273

MonocytesMonocytesCD42CD42 GP1b, FMC-25, Glycophorin A, 10F7

GP1b, FMC-25, Glycophorin A, 10F7

CD56CD56 Leu19, NKH1Leu19, NKH1 Natural killer cellsNatural killer cells

Cytogenetic Abnormalities: Cytogenetic Abnormalities: SignificanceSignificance

Cytogenetic Abnormalities: Cytogenetic Abnormalities: SignificanceSignificance

Cytogenetic AbnormalityCytogenetic Abnormality

Rearrangements of 16q22Rearrangements of 16q22

t(8;21)(q22;q22)t(8;21)(q22;q22)NormalNormalAbnormal 11qAbnormal 11qAbnormal 5 and/or 7Abnormal 5 and/or 7t(15;17)(q22;q11)t(15;17)(q22;q11)

Median Survival(months)

Median Survival(months)

1818

14141010

883322

(Overall Survival in De Novo AML)(Overall Survival in De Novo AML)


French-American-British (FAB) ClassificationFrench-American-British (FAB) ClassificationAML - M0AML - M0 (Acute undifferentiated leukemia) cells

with undifferentiated morphology, with less than 3% MPO positive blasts

(Acute undifferentiated leukemia) cells with undifferentiated morphology, with less than 3% MPO positive blasts

AML - M1AML - M1 30% blasts with 3% MPO positivity, occasionally containing Auer rods, and showing little maturation beyond the myeloblast stage. The blasts can be NASD-negative

30% blasts with 3% MPO positivity, occasionally containing Auer rods, and showing little maturation beyond the myeloblast stage. The blasts can be NASD-negative


French-American-British (FAB) ClassificationFrench-American-British (FAB) Classification

AML-M2AML-M2 >30% myeloblasts ( 3% MPO positive) with > 10% maturing granulocytic elements (progranulocyte through granulocytes) and <20% monocytic cells. Auer rods are often present, and some blasts show NASD positivity. Some cases are associated with t(8;21)

>30% myeloblasts ( 3% MPO positive) with > 10% maturing granulocytic elements (progranulocyte through granulocytes) and <20% monocytic cells. Auer rods are often present, and some blasts show NASD positivity. Some cases are associated with t(8;21)

AML - M3AML - M3 (Acute promyelocytic leukemia, APL) strong MPO positivity, showing a predominance of abnormal promyelocytes, with abnormally heavy granulation and occasional cells with bundles of Auer rods. A microgranular variant lacks the heavy granulation but maintains the other features. Both forms show strong NASD positivity and are associated with t(15;17).

(Acute promyelocytic leukemia, APL) strong MPO positivity, showing a predominance of abnormal promyelocytes, with abnormally heavy granulation and occasional cells with bundles of Auer rods. A microgranular variant lacks the heavy granulation but maintains the other features. Both forms show strong NASD positivity and are associated with t(15;17).


French-American-British (FAB) ClassificationFrench-American-British (FAB) ClassificationAML - M4AML - M4 (Acute myelomonocytic leukemia) MPO positive,

resembles M2 except that 20% of the cells are promonocytes (NSE-positive). A distinct subtype, associated with inv(16), has increased eosinophils with basophilic granules

(Acute myelomonocytic leukemia) MPO positive, resembles M2 except that 20% of the cells are promonocytes (NSE-positive). A distinct subtype, associated with inv(16), has increased eosinophils with basophilic granules

AML - M5AML - M5 (Acute monocytic leukemia) leukemic cells are either monoblasts or promonocytes with abundant cytoplasm and eccentric nuclei. NSE and NASD positive; MPO staining is rare (<3%)

(Acute monocytic leukemia) leukemic cells are either monoblasts or promonocytes with abundant cytoplasm and eccentric nuclei. NSE and NASD positive; MPO staining is rare (<3%)


French-American-British (FAB) ClassificationFrench-American-British (FAB) ClassificationAML - M6AML - M6 (Erythroleukemia) consisted of M1, M2,

or M4 blasts intermingled with dysplastic erythroid precursors, PAS positive

(Erythroleukemia) consisted of M1, M2, or M4 blasts intermingled with dysplastic erythroid precursors, PAS positive

AML - M7AML - M7 (Acute megakaryoblastic leukemia) cytochemical stains are usually negative(Acute megakaryoblastic leukemia) cytochemical stains are usually negative

Adult Acute Lymphocytic Adult Acute Lymphocytic LeukemiaLeukemia


FAB classification:L1: MPO negative , with small cells

predominating

L2: MPO negative, heterogeneous population with larger blasts

L3: Burkitt type, MPO negative, homogeneous population of large blasts

FAB classification:L1: MPO negative , with small cells

predominating

L2: MPO negative, heterogeneous population with larger blasts

L3: Burkitt type, MPO negative, homogeneous population of large blasts



patients older than 15 to 18 years of age biologically different from childhood ALL

Philadelphia chromosome (Ph)-positive is more frequent (15% to 30% v <5%) in adult ALL

Translocations t(1;19) and t(4;11) are less common.

patients older than 15 to 18 years of age biologically different from childhood ALL

Philadelphia chromosome (Ph)-positive is more frequent (15% to 30% v <5%) in adult ALL

Translocations t(1;19) and t(4;11) are less common.

Back to Questions

Treatment of AMLTreatment of AMLTreatment of AMLTreatment of AML

Remission-induction therapy: combination of daunorubicin (45mg / m2 / d for 3 days) and cytarabine (100 to 200mg / m2 / d as continuous IV infusion for 7 days)

Post-remission therapy as:

maintenance therapy

consolidation therapy

intensification therapy

Remission-induction therapy: combination of daunorubicin (45mg / m2 / d for 3 days) and cytarabine (100 to 200mg / m2 / d as continuous IV infusion for 7 days)

Post-remission therapy as:

maintenance therapy

consolidation therapy

intensification therapy

Prognosis: Acute Myelogenous Prognosis: Acute Myelogenous LeukemiaLeukemia

Prognosis: Acute Myelogenous Prognosis: Acute Myelogenous LeukemiaLeukemia

De novo AML has a complete response (CR) rate of 60-75%

Long-term disease free survival occurs in 25-50% of patients in CR

Secondary AML has remission rates of 30-40%; long-term survivorship is unusual unless bone marrow transplantation is used

De novo AML has a complete response (CR) rate of 60-75%

Long-term disease free survival occurs in 25-50% of patients in CR

Secondary AML has remission rates of 30-40%; long-term survivorship is unusual unless bone marrow transplantation is used

Prognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AMLPrognostic Factors in AML

Age Leukemia Leukocytosis CNS disease Cytoreduction

Age Leukemia Leukocytosis CNS disease Cytoreduction

< 45 years De Novo <25,000/mm3

Absent Rapid

< 45 years De Novo <25,000/mm3

Absent Rapid

<2 yrs, >60 yrs Preceding MDS >100,000/mm3

Present Delayed

<2 yrs, >60 yrs Preceding MDS >100,000/mm3

Present Delayed

FactorFactor FavorableFavorable UnfavorableUnfavorable

Greer JP and Kinney MC, Clinical Hematology; 1993Greer JP and Kinney MC, Clinical Hematology; 1993

ClinicalClinical


Auer rods Eosinophils Megaloblastic

erythroids FAB type

Auer rods Eosinophils Megaloblastic

erythroids FAB type

Present Present Absent

M3, M4

Present Present Absent

M3, M4

Absent Absent Present

M5, 6, 7

Absent Absent Present

M5, 6, 7



MorphologyMorphology


Myeloid

HLA-DR TdT Lymphoid

Myeloid

HLA-DR TdT Lymphoid

MY4-, MY7-

Negative Absent OKT11 (CD2),

B4 (CD19)

MY4-, MY7-

Negative Absent OKT11 (CD2),

B4 (CD19)

MY4+(CD14), MY7+(CD13), MY10+(CD34)

Positive Present Biphenotypic ( 2

lymphoid markers)

MY4+(CD14), MY7+(CD13), MY10+(CD34)

Positive Present Biphenotypic ( 2

lymphoid markers)



Surface/Enzyme MarkersSurface/Enzyme Markers


t(15; 17), t(8; 21), inv(16)/del(16q)

t(15; 17), t(8; 21), inv(16)/del(16q)

-7, del(7q); -5, del(5q); 11q23 abnormalities; 3q21 and 3q26 abnormalities

-7, del(7q); -5, del(5q); 11q23 abnormalities; 3q21 and 3q26 abnormalities

FavorableFavorable UnfavorableUnfavorable


CytogeneticsCytogenetics



Complete response rates (CR) range from 65% to 85%, and cure rates from 20% to 35%

Adults with ALL do not tolerate intensive chemotherapy as well as children.

Complete response rates (CR) range from 65% to 85%, and cure rates from 20% to 35%

Adults with ALL do not tolerate intensive chemotherapy as well as children.

Poor Prognostic Factors: ALLPoor Prognostic Factors: ALLPoor Prognostic Factors: ALLPoor Prognostic Factors: ALL

Presence of Ph-positive disease and Burkitt leukemia before the intensive regimen

Older age Leucocytosis

Presence of Ph-positive disease and Burkitt leukemia before the intensive regimen

Older age Leucocytosis

Poor Prognostic FactorsPoor Prognostic FactorsPoor Prognostic FactorsPoor Prognostic Factors

Longer time to achieve complete remission

Non-T-cell immunophenotype Karyotypes: t(9;22) or t(4;11)

Longer time to achieve complete remission

Non-T-cell immunophenotype Karyotypes: t(9;22) or t(4;11)

Treatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALLTreatment of Adult ALL

Induction therapy with vincristine-corticosteroids-anthracyclines is the current standard of care.CR rate of 64% to 87%Combining cyclophosphamide, asparaginase, or

cytarabine does not improve the results except in a subset of patients.

Induction therapy with vincristine-corticosteroids-anthracyclines is the current standard of care.CR rate of 64% to 87%Combining cyclophosphamide, asparaginase, or

cytarabine does not improve the results except in a subset of patients.


Consolidation-intensification with higher doses of asparaginase, 6 mercaptopurine (6MP) plus methotrexate, and cyclophosphamide plus cytarabine improve overall outcome in specific adult ALL subsets (B-cell ALL, T-cell ALL)

Consolidation-intensification with higher doses of asparaginase, 6 mercaptopurine (6MP) plus methotrexate, and cyclophosphamide plus cytarabine improve overall outcome in specific adult ALL subsets (B-cell ALL, T-cell ALL)


Maintenance therapy with 6MP and methotrexate is beneficial except in Burkitt’s and other mature B-cell ALL, and in Ph-positive ALL

Maintenance therapy with 6MP and methotrexate is beneficial except in Burkitt’s and other mature B-cell ALL, and in Ph-positive ALL

Central Nervous System Central Nervous System ProphylaxisProphylaxis

Central Nervous System Central Nervous System ProphylaxisProphylaxis

CNS relapse rate in patients without prophylaxis: 21% to 50%

CNS prophylaxis with intrathecal chemotherapy and high dose systemic therapy using agents with good CNS penetration ( cytarabine, methotrexate, dexamethasone) is sufficient.

Radiation therapy limits the application of high dose chemotherapy and compromises TBI for BMT.

CNS relapse rate in patients without prophylaxis: 21% to 50%

CNS prophylaxis with intrathecal chemotherapy and high dose systemic therapy using agents with good CNS penetration ( cytarabine, methotrexate, dexamethasone) is sufficient.

Radiation therapy limits the application of high dose chemotherapy and compromises TBI for BMT.

Myelodysplastic Syndromes (MDS)Myelodysplastic Syndromes (MDS)Myelodysplastic Syndromes (MDS)Myelodysplastic Syndromes (MDS)

Clonal refractory cytopenias whose marrows show characteristic dysplastic changes in at least 2 of 3 hemopoietic cell lines.

Propensity to transform to acute leukemiaPrimary or secondary (therapy-related)

Clonal refractory cytopenias whose marrows show characteristic dysplastic changes in at least 2 of 3 hemopoietic cell lines.

Propensity to transform to acute leukemiaPrimary or secondary (therapy-related)

Myelodysplastic syndromeMyelodysplastic syndromeMyelodysplastic syndromeMyelodysplastic syndrome

Disease of the elderly More common above 50 years

Relatively common Therapy related MDS not age-related

Late toxicity of cancer treatment: radiation, alkylating agents: busulfan, nitrosourea, procarbazine, DNA topoisomerase inhibitors

Disease of the elderly More common above 50 years

Relatively common Therapy related MDS not age-related

Late toxicity of cancer treatment: radiation, alkylating agents: busulfan, nitrosourea, procarbazine, DNA topoisomerase inhibitors

Clinical presentationClinical presentationClinical presentationClinical presentation

Asymptomatic Symptoms of

Anemia: gradual onset of fatigue, weakness, dyspnea, pallor Some bleeding manifestations

Physical examination Signs of anemia Spenomegaly (20%) commonly in CMML lymphadenopathy is uncommon Unusual skin manifestations (Sweet’s syndrome: febrile neutrophilic

dermatosis) Autoimmune syndromes not infrequent

Asymptomatic Symptoms of

Anemia: gradual onset of fatigue, weakness, dyspnea, pallor Some bleeding manifestations

Physical examination Signs of anemia Spenomegaly (20%) commonly in CMML lymphadenopathy is uncommon Unusual skin manifestations (Sweet’s syndrome: febrile neutrophilic

dermatosis) Autoimmune syndromes not infrequent

Diagnosis of MDSDiagnosis of MDSDiagnosis of MDSDiagnosis of MDS

No single morphologic finding is No single morphologic finding is diagnosticdiagnostic

Combination of dysplastic features in Combination of dysplastic features in the peripheral blood and bone marrow the peripheral blood and bone marrow is necessary.is necessary.

The diagnosis of MDS is a diagnosis The diagnosis of MDS is a diagnosis of exclusion.of exclusion.

No single morphologic finding is No single morphologic finding is diagnosticdiagnostic

Combination of dysplastic features in Combination of dysplastic features in the peripheral blood and bone marrow the peripheral blood and bone marrow is necessary.is necessary.

The diagnosis of MDS is a diagnosis The diagnosis of MDS is a diagnosis of exclusion.of exclusion.

Diagnosis of MDSDiagnosis of MDSDiagnosis of MDSDiagnosis of MDS

The following must always be excluded The following must always be excluded Absolute exclusionsAbsolute exclusions

Vitamin B12 and / or folate deficiencyVitamin B12 and / or folate deficiency Proven exposure to heavy metalsProven exposure to heavy metals Recent cytotoxic therapyRecent cytotoxic therapy

Relative exclusionsRelative exclusions Ongoing inflammation including HIV and Ongoing inflammation including HIV and

cancercancer Chronic liver disease / alcohol useChronic liver disease / alcohol use

The following must always be excluded The following must always be excluded Absolute exclusionsAbsolute exclusions

Vitamin B12 and / or folate deficiencyVitamin B12 and / or folate deficiency Proven exposure to heavy metalsProven exposure to heavy metals Recent cytotoxic therapyRecent cytotoxic therapy

Relative exclusionsRelative exclusions Ongoing inflammation including HIV and Ongoing inflammation including HIV and

cancercancer Chronic liver disease / alcohol useChronic liver disease / alcohol use

Laboratory Studies in MDSLaboratory Studies in MDSLaboratory Studies in MDSLaboratory Studies in MDS

Serum B12 and folate Serum iron and ferritin Iron and reticulin stain of

the marrow Chromosomal studies Flow cytometry

Serum B12 and folate Serum iron and ferritin Iron and reticulin stain of

the marrow Chromosomal studies Flow cytometry

Peripheral Blood and Bone Marrow Peripheral Blood and Bone Marrow FindingsFindings

DyserythropoiesisDyserythropoiesis

Peripheral Blood and Bone Marrow Peripheral Blood and Bone Marrow FindingsFindings

DyserythropoiesisDyserythropoiesis Peripheral blood

Macrocytes Hypochromic microcytes,

poikilocytosis Bone marrow

Megaloblastoid Nuclear-cytoplasmic

asynchrony Cytoplasmic tears or rents Pathologic ringed

sideroblasts

Peripheral blood Macrocytes Hypochromic microcytes,

poikilocytosis Bone marrow

Megaloblastoid Nuclear-cytoplasmic

asynchrony Cytoplasmic tears or rents Pathologic ringed

sideroblasts

Nucleo-cytoplasmic maturation dissociation

Hyposegmentation / hypersegmentation of nucleus

Increase in myeloblasts Abnormal localization of

immature precursors

Nucleo-cytoplasmic maturation dissociation

Hyposegmentation / hypersegmentation of nucleus

Increase in myeloblasts Abnormal localization of

immature precursors

Peripheral Blood and Bone Marrow Findings

Dyserythropoiesis


Dyserythropoiesis


Dysmegakaryocytopoiesis


Dysmegakaryocytopoiesis Peripheral Blood

Thrombocytopenia Giant forms Lack of aggregation

Bone Marrow Mononuclear or bilobed forms Hypersegmented forms Cytoplasmic vacuolization Increase in

micromegakaryocytes

Peripheral Blood Thrombocytopenia Giant forms Lack of aggregation

Bone Marrow Mononuclear or bilobed forms Hypersegmented forms Cytoplasmic vacuolization Increase in

micromegakaryocytes

FISH, MDS FISH, MDS

French - American and British Morphologic French - American and British Morphologic Classification (FAB)Classification (FAB)

French - American and British Morphologic French - American and British Morphologic Classification (FAB)Classification (FAB)

Refractory anemia (RA Refractory anemia (RA) with ringed

sideroblasts (RARS) Chronic myelomonocytic leukemia

(CMML) Refractory anemia with excess of blasts

(RAEB) Refractory anemia with excess of blasts

in transformation (RAEB-T)

Refractory anemia (RA Refractory anemia (RA) with ringed

sideroblasts (RARS) Chronic myelomonocytic leukemia

(CMML) Refractory anemia with excess of blasts

(RAEB) Refractory anemia with excess of blasts

in transformation (RAEB-T)

WHO Classification of MDSWHO Classification of MDSWHO Classification of MDSWHO Classification of MDS

Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts(RARS) Refractory Cytopenia with Multilineage Dysplasia(RCMD) Refractory Cytopenia with Multilineage Dysplasia and

Ringed Sideroblasts (RCMD-RS) Refractory Anemia with Excess Blasts-1(RAEB-1) Refractory Anemia with Excess Blasts-2(RAEB-2) Myelodysplastic Syndrome, Unclassified (MDS-U) Myelodysplastic Syndrome Associated with del (5q)

Refractory Anemia (RA) Refractory Anemia with Ringed Sideroblasts(RARS) Refractory Cytopenia with Multilineage Dysplasia(RCMD) Refractory Cytopenia with Multilineage Dysplasia and

Ringed Sideroblasts (RCMD-RS) Refractory Anemia with Excess Blasts-1(RAEB-1) Refractory Anemia with Excess Blasts-2(RAEB-2) Myelodysplastic Syndrome, Unclassified (MDS-U) Myelodysplastic Syndrome Associated with del (5q)

Follow-up Observations of MDSFollow-up Observations of MDSFollow-up Observations of MDSFollow-up Observations of MDS

Those with stable clinical course with no life threatening cytopenias, follow-up examinations.

Cytogenetic studies may show change in karyotype; clonal evolution suggestive of imminent leukemic transformation.

Those with stable clinical course with no life threatening cytopenias, follow-up examinations.

Cytogenetic studies may show change in karyotype; clonal evolution suggestive of imminent leukemic transformation.

Immunological Abnormalities in Immunological Abnormalities in MDSMDS

Immunological Abnormalities in Immunological Abnormalities in MDSMDS

ImmunoglobulinsPolyclonal

hypergammaglobulinemiaHypogammaglobulinemiaMonoclonal gammopathyAnti-red cell antibodies

B cellsNormal in numberFunctionally immature

ImmunoglobulinsPolyclonal

hypergammaglobulinemiaHypogammaglobulinemiaMonoclonal gammopathyAnti-red cell antibodies

B cellsNormal in numberFunctionally immature

International Prognostic Scoring International Prognostic Scoring System: MDSSystem: MDS

International Prognostic Scoring International Prognostic Scoring System: MDSSystem: MDS

Prognostic variable

Score Value

0 0.5 1.0 1.5 2.0

Bone marrow blasts

<5% 5-10%

11-20 21-30

Karyotype good intermediate

poor

Cytopenia 0 or 1

2 or 3

Risk group scores

Score

Low 0

Intermediate-1 0.5-1.0

Intermediate-2 1.5-2.0

High >2.5

Therapy of MDSTherapy of MDSTherapy of MDSTherapy of MDS

Standard therapy: supportive careAnemia may be treated with transfusionJudicious use of red cell and platelet

transfusions to minimize the risk of alloimmunization

Erythropoietin may be successful in low erythropoietin states

Antibiotics when indicated

Standard therapy: supportive careAnemia may be treated with transfusionJudicious use of red cell and platelet

transfusions to minimize the risk of alloimmunization

Erythropoietin may be successful in low erythropoietin states

Antibiotics when indicated

Treatment of MDSTreatment of MDSTreatment of MDSTreatment of MDS

Factors to be considered: clinical severity and patient age

Stable process: no treatment

Factors to be considered: clinical severity and patient age

Stable process: no treatment

Treatment of MDSTreatment of MDSTreatment of MDSTreatment of MDS

Treatment with hematopoietic growth factors (G-CSF, GM-CSF, IL-3)

Low-dose Ara-C, retinoids Bone marrow transplantation Aggressive anti-leukemic therapy

Treatment with hematopoietic growth factors (G-CSF, GM-CSF, IL-3)

Low-dose Ara-C, retinoids Bone marrow transplantation Aggressive anti-leukemic therapy

Novel TreatmentsNovel TreatmentsNovel TreatmentsNovel Treatments

Anti-angiogenic : Thalidomide, lenalidomide, bevacizumab, arsenic trioxide

Tyrosine kinase inhibitors: Glivec Farnesyl transferase inhibitors: tipifarnib DNA methylation inhibitors: azacytidine,

deoxycytidine

Anti-angiogenic : Thalidomide, lenalidomide, bevacizumab, arsenic trioxide

Tyrosine kinase inhibitors: Glivec Farnesyl transferase inhibitors: tipifarnib DNA methylation inhibitors: azacytidine,

deoxycytidine

Case 2-02-01Case 2-02-01Case 2-02-01Case 2-02-01 55 year old female was referred because of hemoglobin of 19 mg/dL and

hematocrit of 56 cv% admitted because of right sided extremity weakness, dizziness and

headache and was diagnosed to have left cerebral infarction ROS: occasional pruritus no prior history of hypertension or diabetes mellitus did not take contraceptive pills postmenopausic, G3P3 family history of hypertension, no cancer Physical examination

facial plethora splenomegaly neurologic deficits as described

55 year old female was referred because of hemoglobin of 19 mg/dL and hematocrit of 56 cv%

admitted because of right sided extremity weakness, dizziness and headache and was diagnosed to have left cerebral infarction

ROS: occasional pruritus no prior history of hypertension or diabetes mellitus did not take contraceptive pills postmenopausic, G3P3 family history of hypertension, no cancer Physical examination

facial plethora splenomegaly neurologic deficits as described


What are the signs and symptoms of erythrocytosis? What are the causes of secondary erythrocytosis? What is polycythemia rubra vera? What are the laboratory abnormalities in polycythemia

vera? W hat are the diagnostic criteria for polycythemia vera? How do you How do you manage this patient?this patient? What are the What are the complications associated with this condition? associated with this condition?

What are the signs and symptoms of erythrocytosis? What are the causes of secondary erythrocytosis? What is polycythemia rubra vera? What are the laboratory abnormalities in polycythemia

vera? W hat are the diagnostic criteria for polycythemia vera? How do you How do you manage this patient?this patient? What are the What are the complications associated with this condition? associated with this condition?

Polycythemia Rubra VeraPolycythemia Rubra VeraPolycythemia Rubra VeraPolycythemia Rubra Vera

Myeloproliferative disorder affecting mainly red blood cells

Incidence varies considerably in different parts of the world

Age incidence: 6th and 7th decades of life No obvious causative agent identifiable in

majority of patients

Myeloproliferative disorder affecting mainly red blood cells

Incidence varies considerably in different parts of the world

Age incidence: 6th and 7th decades of life No obvious causative agent identifiable in

majority of patients

Polycythemia Rubra VeraPolycythemia Rubra VeraPathophysiologyPathophysiology

Polycythemia Rubra VeraPolycythemia Rubra VeraPathophysiologyPathophysiology

primary defect involves a pluripotent stem cell capable of differentiating into both myeloid and lymphoid cells.

Increased sensitivity to EPO, interleukin-3 (IL-3), GM-CSF Alteration or activation of the EPO receptor Alteration or activation of the EPO receptor

gives rise to autonomous erythropoiesisgives rise to autonomous erythropoiesis Lack of negative feedback mechanisms

primary defect involves a pluripotent stem cell capable of differentiating into both myeloid and lymphoid cells.

Increased sensitivity to EPO, interleukin-3 (IL-3), GM-CSF Alteration or activation of the EPO receptor Alteration or activation of the EPO receptor

gives rise to autonomous erythropoiesisgives rise to autonomous erythropoiesis Lack of negative feedback mechanisms

Back to Questions

Polycythemia Rubra VeraPolycythemia Rubra VeraClinical FeaturesClinical Features

Polycythemia Rubra VeraPolycythemia Rubra VeraClinical FeaturesClinical Features

Headache Dyspnea Weakness Sweating Weight loss Plethora Dizziness Visual changes

Headache Dyspnea Weakness Sweating Weight loss Plethora Dizziness Visual changes

Epistaxis Angina Pruritus Paresthesia Gout Splenomegaly Hypertension Leg ulcers

Epistaxis Angina Pruritus Paresthesia Gout Splenomegaly Hypertension Leg ulcers

Back to Questions

Polycythemia Rubra VeraPolycythemia Rubra VeraLaboratory AbnormalitiesLaboratory Abnormalities

Polycythemia Rubra VeraPolycythemia Rubra VeraLaboratory AbnormalitiesLaboratory Abnormalities

Erythrocytosis, leucocytosis, thrombocytosis Hyperuricemia Elevated leucocyte alkaline phosphatase pO2 > 92% Elevated LDH Elevated B12, unbound B12 binding

capacity

Erythrocytosis, leucocytosis, thrombocytosis Hyperuricemia Elevated leucocyte alkaline phosphatase pO2 > 92% Elevated LDH Elevated B12, unbound B12 binding

capacity

PRVPRVPRVPRV

Peripheral blood Bone marrow biopsy

Back to Questions

Polycythemia Rubra VeraPolycythemia Rubra VeraDiagnostic CriteriaDiagnostic Criteria

Polycythemia Rubra VeraPolycythemia Rubra VeraDiagnostic CriteriaDiagnostic Criteria

Major Criteria A1 Hematocrit > 60% or rbc

mass (ml/kg) > 36 in males and >32 in females

A 2 Arterial O2 saturation of >95%

A 3 Splenomegaly

Major Criteria A1 Hematocrit > 60% or rbc

mass (ml/kg) > 36 in males and >32 in females

A 2 Arterial O2 saturation of >95%

A 3 Splenomegaly

Polycythemia Rubra VeraDiagnostic Criteria


Minor CriteriaMinor Criteria B1 B1 Platelet count >400,000/uLPlatelet count >400,000/uL B2 B2 WBC >12,000/uLWBC >12,000/uL B3 B3 Leucocyte alkaline Leucocyte alkaline

phosphatase >100phosphatase >100 B4 B4 Unbound vit B12 binding Unbound vit B12 binding

capacity >2,200pg/mLcapacity >2,200pg/mL

Minor CriteriaMinor Criteria B1 B1 Platelet count >400,000/uLPlatelet count >400,000/uL B2 B2 WBC >12,000/uLWBC >12,000/uL B3 B3 Leucocyte alkaline Leucocyte alkaline

phosphatase >100phosphatase >100 B4 B4 Unbound vit B12 binding Unbound vit B12 binding

capacity >2,200pg/mLcapacity >2,200pg/mL



Diagnosis is acceptable if:Diagnosis is acceptable if: A1 + A2 + A3 orA1 + A2 + A3 or A1 + A2 + any two from A1 + A2 + any two from

category Bcategory B

Diagnosis is acceptable if:Diagnosis is acceptable if: A1 + A2 + A3 orA1 + A2 + A3 or A1 + A2 + any two from A1 + A2 + any two from

category Bcategory B

Back to Questions

Differential Diagnosis of Differential Diagnosis of PolycythemiaPolycythemia

Differential Diagnosis of Differential Diagnosis of PolycythemiaPolycythemia

Spurious polycythemia Secondary polycythemia Polycythemia Vera

Spurious polycythemia Secondary polycythemia Polycythemia Vera

Back to Questions

Secondary PolycythemiaSecondary PolycythemiaSecondary PolycythemiaSecondary PolycythemiaInappropriate Renal cysts, hydronephrosis Tumors

Renal Uterine myoma Hepatoma Cerebellar hemangioma

Inappropriate Renal cysts, hydronephrosis Tumors

Renal Uterine myoma Hepatoma Cerebellar hemangioma

Secondary PolycythemiaSecondary PolycythemiaAppropriateAppropriate Arterial hypoxemiaArterial hypoxemia

High altitudeHigh altitude Right-to-left shuntRight-to-left shunt Lung diseaseLung disease Liver cirrhosisLiver cirrhosis

Defective oxygen deliveryDefective oxygen delivery Congenital abnormal hemoglobinCongenital abnormal hemoglobin CarboxyhemoglobinCarboxyhemoglobin

AppropriateAppropriate Arterial hypoxemiaArterial hypoxemia

High altitudeHigh altitude Right-to-left shuntRight-to-left shunt Lung diseaseLung disease Liver cirrhosisLiver cirrhosis

Defective oxygen deliveryDefective oxygen delivery Congenital abnormal hemoglobinCongenital abnormal hemoglobin CarboxyhemoglobinCarboxyhemoglobin

Back to Polycythemia vera

Polycythemia VeraPolycythemia VeraTreatmentTreatment

Polycythemia VeraPolycythemia VeraTreatmentTreatment

Removal of red cells through phlebotomy until the hematocrit is in the normal range.

Myelosuppressive drugs: hydroxyurea, busulfan, interferons

Anti-thrombotic therapy

Removal of red cells through phlebotomy until the hematocrit is in the normal range.

Myelosuppressive drugs: hydroxyurea, busulfan, interferons

Anti-thrombotic therapy

Polycythemia Rubra VeraPolycythemia Rubra VeraCourseCourse

Polycythemia Rubra VeraPolycythemia Rubra VeraCourseCourse

15% will develop postpolycythemia myeloid metaplasia (PPMM), also termed the spent phase due to the waning of bone marrow proliferative activity.Appears at an average interval of 10 yearsNo effective therapy for this phase

Transformation to acute leukemia is a frequent cause of death

15% will develop postpolycythemia myeloid metaplasia (PPMM), also termed the spent phase due to the waning of bone marrow proliferative activity.Appears at an average interval of 10 yearsNo effective therapy for this phase

Transformation to acute leukemia is a frequent cause of death

Back to Questions

Polycythemia Rubra VeraPolycythemia Rubra VeraThrombo-Hemorrhagic ComplicationsThrombo-Hemorrhagic Complications

Polycythemia Rubra VeraPolycythemia Rubra VeraThrombo-Hemorrhagic ComplicationsThrombo-Hemorrhagic Complications

Cerebral thrombosisCerebral thrombosis Coronary thrombosisCoronary thrombosis Peripheral vascular Peripheral vascular

diseasedisease Budd-Chiari Budd-Chiari

syndromesyndrome ErythromelalgiaErythromelalgia Mesenteric vein Mesenteric vein

thrombosisthrombosis

Cerebral thrombosisCerebral thrombosis Coronary thrombosisCoronary thrombosis Peripheral vascular Peripheral vascular

diseasedisease Budd-Chiari Budd-Chiari

syndromesyndrome ErythromelalgiaErythromelalgia Mesenteric vein Mesenteric vein

thrombosisthrombosis

Raynaud’s Raynaud’s phenomenonphenomenon

Monocular blindnessMonocular blindness Spontaneous abortionSpontaneous abortion Cardiac valve Cardiac valve

abnormalitiesabnormalities Cerebral hemorrhageCerebral hemorrhage GI bleedingGI bleeding

Raynaud’s Raynaud’s phenomenonphenomenon

Monocular blindnessMonocular blindness Spontaneous abortionSpontaneous abortion Cardiac valve Cardiac valve

abnormalitiesabnormalities Cerebral hemorrhageCerebral hemorrhage GI bleedingGI bleeding

Myeloproliferative Myeloproliferative Disorders Disorders

Myeloproliferative Myeloproliferative Disorders Disorders

Polycythemia Rubra Vera Primary (Essential)

Thrombocythemia Chronic Myelogenous Leukemia Agnogenic Myeloid Metaplasia

Polycythemia Rubra Vera Primary (Essential)

Thrombocythemia Chronic Myelogenous Leukemia Agnogenic Myeloid Metaplasia

Essential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaEssential (Primary) Thrombocythemia

Clonal myeloid disorder characterized primarily by thrombocytosis

Median age at diagnosis is 60 years

Clonal myeloid disorder characterized primarily by thrombocytosis

Median age at diagnosis is 60 years

Essential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaNatural HistoryNatural History

Essential (Primary) ThrombocythemiaEssential (Primary) ThrombocythemiaNatural HistoryNatural History

Morbidity results from thrombohemorrhagic complications

5% transforms to acute leukemia 5 - 10% develop rises in hemoglobin

and hematocrit in to the PV range

Morbidity results from thrombohemorrhagic complications

5% transforms to acute leukemia 5 - 10% develop rises in hemoglobin

and hematocrit in to the PV range

Essential (Primary) ThrombocythemiaDiagnostic Criteria


Platelet count > 600,000/uLPlatelet count > 600,000/uL No cause for reactive thrombocytosisNo cause for reactive thrombocytosis Hematocrit < 40% or red cell mass < 36 Hematocrit < 40% or red cell mass < 36

for males and < 32 for femalesfor males and < 32 for females Normal red cell MCV or serum ferritin or Normal red cell MCV or serum ferritin or

marrow iron storesmarrow iron stores

Platelet count > 600,000/uLPlatelet count > 600,000/uL No cause for reactive thrombocytosisNo cause for reactive thrombocytosis Hematocrit < 40% or red cell mass < 36 Hematocrit < 40% or red cell mass < 36

for males and < 32 for femalesfor males and < 32 for females Normal red cell MCV or serum ferritin or Normal red cell MCV or serum ferritin or

marrow iron storesmarrow iron stores



Collagen fibrosis of marrow absent or < Collagen fibrosis of marrow absent or < 1/3 of biopsy area without both 1/3 of biopsy area without both splenomegaly and leucoerythroblastic splenomegaly and leucoerythroblastic reactionreaction

No myelodysplastic changes on marrow No myelodysplastic changes on marrow smearsmear

No Philadelphia chromosome or bcr/abl No Philadelphia chromosome or bcr/abl gene rearrangement gene rearrangement

Collagen fibrosis of marrow absent or < Collagen fibrosis of marrow absent or < 1/3 of biopsy area without both 1/3 of biopsy area without both splenomegaly and leucoerythroblastic splenomegaly and leucoerythroblastic reactionreaction

No myelodysplastic changes on marrow No myelodysplastic changes on marrow smearsmear

No Philadelphia chromosome or bcr/abl No Philadelphia chromosome or bcr/abl gene rearrangement gene rearrangement

Essential ThrombocytosisEssential ThrombocytosisEssential ThrombocytosisEssential Thrombocytosis

Reactive (secondary) Reactive (secondary) ThrombocytosisThrombocytosis


Infectious or inflammatory statesInfectious or inflammatory states Surgical procedure and tissue damageSurgical procedure and tissue damage MalignancyMalignancy Iron deficiency anemia, hemolytic anemia, Iron deficiency anemia, hemolytic anemia,

acute blood lossacute blood loss

Infectious or inflammatory statesInfectious or inflammatory states Surgical procedure and tissue damageSurgical procedure and tissue damage MalignancyMalignancy Iron deficiency anemia, hemolytic anemia, Iron deficiency anemia, hemolytic anemia,

acute blood lossacute blood loss

Postsplenectomy statePostsplenectomy state Rebound effect after chemotherapy or Rebound effect after chemotherapy or

immune thrombocytopeniaimmune thrombocytopenia Renal disorders (renal failure, nephrotic Renal disorders (renal failure, nephrotic

syndrome) syndrome)

Postsplenectomy statePostsplenectomy state Rebound effect after chemotherapy or Rebound effect after chemotherapy or

immune thrombocytopeniaimmune thrombocytopenia Renal disorders (renal failure, nephrotic Renal disorders (renal failure, nephrotic

syndrome) syndrome)



Essential (Primary) ThrombocythemiaPathophysiology

Essential (Primary) ThrombocythemiaPathophysiology

Primary platelet overproduction from clonally Primary platelet overproduction from clonally proliferating megakaryocytesproliferating megakaryocytes

In contrast, reactive thrombocytosis is In contrast, reactive thrombocytosis is related to overproduction of interleukin-6 related to overproduction of interleukin-6 ( IL-6) ( IL-6)

during the acute phase responseduring the acute phase response chronic conditions associated with infection, chronic conditions associated with infection,

inflammation, malignancyinflammation, malignancy

Primary platelet overproduction from clonally Primary platelet overproduction from clonally proliferating megakaryocytesproliferating megakaryocytes

In contrast, reactive thrombocytosis is In contrast, reactive thrombocytosis is related to overproduction of interleukin-6 related to overproduction of interleukin-6 ( IL-6) ( IL-6)

during the acute phase responseduring the acute phase response chronic conditions associated with infection, chronic conditions associated with infection,

inflammation, malignancyinflammation, malignancy

Essential (Primary) ThrombocythemiaTherapy

Essential (Primary) ThrombocythemiaTherapy

Platelet-lowering therapyPlatelet-lowering therapy HydroxyureaHydroxyurea AnagrelideAnagrelide InterferonsInterferons

Platelet pheresisPlatelet pheresis Anti-thrombotic therapy Anti-thrombotic therapy

Platelet-lowering therapyPlatelet-lowering therapy HydroxyureaHydroxyurea AnagrelideAnagrelide InterferonsInterferons

Platelet pheresisPlatelet pheresis Anti-thrombotic therapy Anti-thrombotic therapy

Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaPathogenesisPathogenesis

Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaPathogenesisPathogenesis

Primary process: neoplasia of the hematopoietic stem cell

Second aspect of the disease is bone marrow fibrosis, consisting primarily of type I and type III collagen

Primary process: neoplasia of the hematopoietic stem cell

Second aspect of the disease is bone marrow fibrosis, consisting primarily of type I and type III collagen

Agnogenic Myeloid MetaplasiaPathogenesis

Agnogenic Myeloid MetaplasiaPathogenesis

Bone marrow fibrosis Bone marrow fibrosis reactive process that is the result of reactive process that is the result of

functional and kinetic stimulation of functional and kinetic stimulation of nonclonal fibroblasts by growth factors nonclonal fibroblasts by growth factors shed from clonal megakaryocytesshed from clonal megakaryocytes

mediated predominantly by transforming mediated predominantly by transforming growth factor-growth factor-ßß (TGF- (TGF-ßß))

Others: platelet-derived growth factor Others: platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)(PDGF) and epidermal growth factor (EGF)

Bone marrow fibrosis Bone marrow fibrosis reactive process that is the result of reactive process that is the result of

functional and kinetic stimulation of functional and kinetic stimulation of nonclonal fibroblasts by growth factors nonclonal fibroblasts by growth factors shed from clonal megakaryocytesshed from clonal megakaryocytes

mediated predominantly by transforming mediated predominantly by transforming growth factor-growth factor-ßß (TGF- (TGF-ßß))

Others: platelet-derived growth factor Others: platelet-derived growth factor (PDGF) and epidermal growth factor (EGF)(PDGF) and epidermal growth factor (EGF)

Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaClinical FeaturesClinical Features

Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaClinical FeaturesClinical Features

Symptoms secondary to anemia and Symptoms secondary to anemia and marked splenomegalymarked splenomegaly

Leucoerythroblastosis and Leucoerythroblastosis and dacryocytosisdacryocytosis

Hypermetabolism: weight loss, night Hypermetabolism: weight loss, night sweats and feversweats and fever

Symptoms secondary to anemia and Symptoms secondary to anemia and marked splenomegalymarked splenomegaly

Leucoerythroblastosis and Leucoerythroblastosis and dacryocytosisdacryocytosis

Hypermetabolism: weight loss, night Hypermetabolism: weight loss, night sweats and feversweats and fever

Agnogenic Myeloid MetaplasiaClinical Features

Agnogenic Myeloid MetaplasiaClinical Features

Hepatomegaly in 50%Hepatomegaly in 50% Bleeding tendencies secondary to Bleeding tendencies secondary to

intrinsic platelet dysfunction, acquired intrinsic platelet dysfunction, acquired Factor V deficiency, DICFactor V deficiency, DIC

Extramedullary hematopoiesisExtramedullary hematopoiesis Accelerated bone turnover Accelerated bone turnover

demonstrated as increased bone density demonstrated as increased bone density

Hepatomegaly in 50%Hepatomegaly in 50% Bleeding tendencies secondary to Bleeding tendencies secondary to

intrinsic platelet dysfunction, acquired intrinsic platelet dysfunction, acquired Factor V deficiency, DICFactor V deficiency, DIC

Extramedullary hematopoiesisExtramedullary hematopoiesis Accelerated bone turnover Accelerated bone turnover

demonstrated as increased bone density demonstrated as increased bone density

Agnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaAgnogenic Myeloid MetaplasiaAgnogenic Myeloid Metaplasia

Peripheral blood Bone marrow biopsy Bone marrow biopsy, Reticulin stain

Agnogenic Myeloid MetaplasiaPrognosis

Agnogenic Myeloid MetaplasiaPrognosis

Median survival: 5 yearsMedian survival: 5 years No curative therapy currently availableNo curative therapy currently available PalliationPalliation

Androgen therapyAndrogen therapyDanazolDanazolHydroxyureaHydroxyureaSplenectomySplenectomyRadiation treatment Radiation treatment

Median survival: 5 yearsMedian survival: 5 years No curative therapy currently availableNo curative therapy currently available PalliationPalliation

Androgen therapyAndrogen therapyDanazolDanazolHydroxyureaHydroxyureaSplenectomySplenectomyRadiation treatment Radiation treatment

Chronic Myelogenous LeukemiaChronic Myelogenous LeukemiaChronic Myelogenous LeukemiaChronic Myelogenous Leukemia

Clonal MPD of a pluripotent stem cell with a specific cytogenetic abnormality: the Philadelphia chromosome

A causative factor can not be identified

The first phase of the disease, the chronic phase, terminates in a second, more acute course, the blastic phase. There may be an intervening accelerated phase in between.

Clonal MPD of a pluripotent stem cell with a specific cytogenetic abnormality: the Philadelphia chromosome

A causative factor can not be identified

The first phase of the disease, the chronic phase, terminates in a second, more acute course, the blastic phase. There may be an intervening accelerated phase in between.

Chronic Myelogenous LeukemiaClinical and Hematologic Features

Chronic Myelogenous LeukemiaClinical and Hematologic Features

Fatigue, anemia, progressive splenomegaly, Fatigue, anemia, progressive splenomegaly, leucocytosisleucocytosis

Myeloid cells in the peripheral blood show all Myeloid cells in the peripheral blood show all stages of differentiationstages of differentiation

Basophils and eosinophils are increasedBasophils and eosinophils are increased Reduction in leucocyte alkaline phosphatase Reduction in leucocyte alkaline phosphatase

(LAP)(LAP) Hypercellular bone marrow Hypercellular bone marrow

Fatigue, anemia, progressive splenomegaly, Fatigue, anemia, progressive splenomegaly, leucocytosisleucocytosis

Myeloid cells in the peripheral blood show all Myeloid cells in the peripheral blood show all stages of differentiationstages of differentiation

Basophils and eosinophils are increasedBasophils and eosinophils are increased Reduction in leucocyte alkaline phosphatase Reduction in leucocyte alkaline phosphatase

(LAP)(LAP) Hypercellular bone marrow Hypercellular bone marrow

CML, peripheral bloodCML, peripheral bloodCML, peripheral bloodCML, peripheral bloodA: myeloblasts

B: Neutrophilic myelocyte

C:Neutrophilic metamyelocyte

D: Band

E: Basophil

CML, cytogeneticsCML, cytogeneticsCML, cytogeneticsCML, cytogenetics

CML, cytogenetic abnormalityCML, cytogenetic abnormalityCML, cytogenetic abnormalityCML, cytogenetic abnormality

Chronic Myelogenous LeukemiaTreatment

Chronic Myelogenous LeukemiaTreatment

Allogeneic stem cell transplantation Imatinib: tyrosine kinase inhibitor Interferon Hydroxyurea Busulfan

Allogeneic stem cell transplantation Imatinib: tyrosine kinase inhibitor Interferon Hydroxyurea Busulfan

Case 2-03-01Case 2-03-01Case 2-03-01Case 2-03-01 70 year old male presented with masses in both sides of his neck of one

year duration gradual weight loss, low grade fever, anorexia and body weakness no cough, shortness of breath, abdominal pain and leg swelling PE: BP: 120/80 PR: 87/min, RR: 20/min, Temp: 38’C.

not pale, no jaundice bilateral cervical lymph nodes, the largest measuring 3 x 2 cm, discrete,

nontender and movable mass in the right axilla of the same character no inguinal lymph nodes heart and lung examination were normal spleen was palpable 3 cm below the left subcostal margin at the

midclavicular line no pedal edema

70 year old male presented with masses in both sides of his neck of one year duration

gradual weight loss, low grade fever, anorexia and body weakness no cough, shortness of breath, abdominal pain and leg swelling PE: BP: 120/80 PR: 87/min, RR: 20/min, Temp: 38’C.

not pale, no jaundice bilateral cervical lymph nodes, the largest measuring 3 x 2 cm, discrete,

nontender and movable mass in the right axilla of the same character no inguinal lymph nodes heart and lung examination were normal spleen was palpable 3 cm below the left subcostal margin at the

midclavicular line no pedal edema


What are the possible causes of lymphadenopathy in this patient?

How would you establish the diagnosis? What are the examinations necessary for

diagnosis and staging? What are the What are the types of lymphoma?of lymphoma? What is the What is the treatments available for patients s available for patients

with lymphoma?with lymphoma?

What are the possible causes of lymphadenopathy in this patient?

How would you establish the diagnosis? What are the examinations necessary for

diagnosis and staging? What are the What are the types of lymphoma?of lymphoma? What is the What is the treatments available for patients s available for patients

with lymphoma?with lymphoma?

Lymphoproliferative DisordersLymphoproliferative DisordersLymphoproliferative DisordersLymphoproliferative Disorders

Heterogenous group of diseases with protean manifestations Lymph node enlargement Bone marrow involvement

Anemia, lymphocytosis, thrombocytopenia

Involvement of secondary lymphoid organs Constitutional “B” symptoms: fever, weight loss,

night sweats, pruritus

Heterogenous group of diseases with protean manifestations Lymph node enlargement Bone marrow involvement

Anemia, lymphocytosis, thrombocytopenia

Involvement of secondary lymphoid organs Constitutional “B” symptoms: fever, weight loss,

night sweats, pruritus

Back to Questions

Diseases/ Exposures Associated with Diseases/ Exposures Associated with Increased Risk of LymphomaIncreased Risk of Lymphoma

Inherited immunodeficiency disease Klinefelter’s syndrome Chediak Hegashi syndrome Ataxia telagiectasia syndrome Wiskott-Aldrich syndrome Common variable

immunodefiency disease Acquired immunodeficiency

Iatrogenic immunosuppression HIV-1 infection Acquired

hypogammaglobulinemia

Autoimmune disease Sjogren’s syndrome Celiac sprue Rheumatoid arthritis Systemic lupus

erythematosus Chemical or Drug exposures

Phenytoin Dioxin, phenoherbicides Radiation Prior chemotherapy &

radiation therapy

Agent Lymphoid Malignancy

Epstein Barr virus Burkitt’s lymphoma

Post-transplant lymphoma

Primary CNS Diffuse large B cell lymphoma

Hodgkin’s disease

Extranodal NK/T cell lymphoma, nasal type

HTLV-1 Adult T-cell leukemia/lymphoma

Human Herpes Virus-8 multicentric Castleman's disease

Primary effusion lymphoma

Hepatitis C virus (HCV) essential mixed cryoglobulinemia

monocytoid B-cell lymphoma lymphoplasmacytoid lymphoma

Helicobacter pylori gastric MALT lymphoma

Infectious AgentsInfectious Agents

A properly done biopsy is extremely A properly done biopsy is extremely important in the diagnosis of lymphomaimportant in the diagnosis of lymphoma

A properly done biopsy is extremely A properly done biopsy is extremely important in the diagnosis of lymphomaimportant in the diagnosis of lymphoma

Benign reactive lymph node Follicular, small cleaved cell (NHL)

Diffuse small lymphocytic (NHL) Diffuse large cell (NHL)

Back

Diagnosis of Hodgkin’s Diagnosis of Hodgkin’s DiseaseDisease

Diagnosis of Hodgkin’s Diagnosis of Hodgkin’s DiseaseDisease

The presence of the Reed-Sternberg cell is a sine qua non for the diagnosis of Hodgkin’s disease

Evaluation for Diagnosis & Evaluation for Diagnosis & StagingStaging

Evaluation for Diagnosis & Evaluation for Diagnosis & StagingStaging

Complete blood count ESR Biochemical studies of major

organ function For NHL

SLDH B2 microglobulin Serum protein electrophoresis

Excision biopsy of lymph node Flow cytometry IHC Cytogenetics

Complete blood count ESR Biochemical studies of major

organ function For NHL

SLDH B2 microglobulin Serum protein electrophoresis

Excision biopsy of lymph node Flow cytometry IHC Cytogenetics

Imaging studies Contrast-enhanced CT scan

of the chest and whole abdomen

MRI if indicated Gallium scan not necessary

for primary staging PET scan

Bone marrow aspiration and biopsy

Imaging studies Contrast-enhanced CT scan

of the chest and whole abdomen

MRI if indicated Gallium scan not necessary

for primary staging PET scan

Bone marrow aspiration and biopsy

Back

Revised European-American Lymphoma Revised European-American Lymphoma (REAL)/WHO Classification(REAL)/WHO Classification

Revised European-American Lymphoma Revised European-American Lymphoma (REAL)/WHO Classification(REAL)/WHO Classification

B cell neoplasms Precursor B-cell neoplasm

Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)

Mature (peripheral) B-cell neoplasms Chronic lymphocytic leukemia/B-cell small

lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma

(splenic lymphoma with villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma

(MALT lymphoma) Nodal marginal zone B-cell lymphomaFollicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphomas Burkitt's lymphoma/leukemia

B cell neoplasms Precursor B-cell neoplasm

Precursor B-lymphoblastic leukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia)

Mature (peripheral) B-cell neoplasms Chronic lymphocytic leukemia/B-cell small

lymphocytic lymphoma B-cell prolymphocytic leukemia Lymphoplasmacytic lymphoma Splenic marginal zone B-cell lymphoma

(splenic lymphoma with villous lymphocytes) Hairy cell leukemia Plasma cell myeloma/plasmacytoma Extranodal marginal zone B-cell lymphoma

(MALT lymphoma) Nodal marginal zone B-cell lymphomaFollicular lymphoma Mantle cell lymphoma Diffuse large B-cell lymphomas Burkitt's lymphoma/leukemia

T- and NK-cell neoplasms Precursor T-cell neoplasm

Precursor T-lymphoblastic leukemia/lymphoma (precursor T-cell acute lymphoblastic leukemia)

Blastoid NK cell lymphoma Mature (peripheral) T-cell neoplasms

T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T-cell lymphoma/leukemia (HTLV-1+) Extranodal NK/T-cell lymphoma, nasal type nteropathy-type T-cell lymphomaHepato splenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary syndrome Primary cutaneous anaplastic large cell

lymphoma Peripheral T-cell lymphoma, not otherwise

specified Angioimmunoblastic T-cell lymphoma Primary systemic anaplastic large cell

lymphoma

T- and NK-cell neoplasms Precursor T-cell neoplasm

Precursor T-lymphoblastic leukemia/lymphoma (precursor T-cell acute lymphoblastic leukemia)

Blastoid NK cell lymphoma Mature (peripheral) T-cell neoplasms

T-cell prolymphocytic leukemia T-cell large granular lymphocytic leukemia Aggressive NK cell leukemia Adult T-cell lymphoma/leukemia (HTLV-1+) Extranodal NK/T-cell lymphoma, nasal type nteropathy-type T-cell lymphomaHepato splenic T-cell lymphoma Subcutaneous panniculitis-like T-cell lymphoma Mycosis fungoides/Sézary syndrome Primary cutaneous anaplastic large cell

lymphoma Peripheral T-cell lymphoma, not otherwise

specified Angioimmunoblastic T-cell lymphoma Primary systemic anaplastic large cell

lymphoma

Table 41.5-2: Classifications of Hodgkin's Lymphoma (HL)

Jackson and Parkera

Lukes and Butlerb Rye Conferencec REAL Classificationd WHO Classificatione

Paragranuloma Lymphocytic and/or histiocytic, nodular

Lymphocyte predominant

Nodular lymphocyte predominant

Lymphocyte predominant, nodular

Lymphocytic and/or histiocytic, diffuse

Classic HL Classic HL

Lymphocyte-rich classic HLf

Lymphocyte-rich classic HL

Granuloma Nodular sclerosis Nodular sclerosis Nodular sclerosis Nodular sclerosis

Mixed cellularityg Mixed cellularityg Mixed cellularity Mixed cellularity

Sarcoma Diffuse fibrosis Lymphocytic depleted

Lymphocyte depleted Lymphocyte depleted

Reticular Unclassifiable classic HL

Classification of Hodgkin’s Classification of Hodgkin’s LymphomaLymphoma

Classification of Hodgkin’s Classification of Hodgkin’s LymphomaLymphoma

Histologic subtypes of Hodgkin’s Histologic subtypes of Hodgkin’s DiseaseDisease

Histologic subtypes of Hodgkin’s Histologic subtypes of Hodgkin’s DiseaseDisease

Lymphocytic predominance

Mixed Cellularity

Nodular sclerosis

Lymphocyte depletion

Disease Cytogenetic abnormality

Oncogene

CLL/ Small lymphocytic lymphoma

t(14;15)(q32;q13)

MALT lymphoma t(11;18)(q21;q21)

Precursor B cell acute lymphoid leukemia

t(9;22)(q34;q11)

t(12;21)(p12;q22)

11q23/MLL

BCR/ABL

ETV6

ETV6-CBFA2 TEL-AML1

Molecular MarkersMolecular Markers

Disease Cytogenetic abnormality

Oncogene

Mantle cell lymphoma

t(11;14)(q13;q32) BCL-1

Follicular lymphoma t(14;18)(q32;q21) BCL-2

Diffuse large cell lymphoma

t(3;-)(q27;-)

t(17;-)(p13;-)

BCL-6

p53

Burkitt’s lymphoma t(8;-)(q24;-) C-MYC

Anaplastic large cell lymphoma

t(2;5)(q23;q35) ALK

Lymphoplasmacytoid lymphoma

t(9:14)(p13;q32)

Molecular MarkersMolecular Markers

Back to Questions

Histologic subtype of lymphoma Indolent vs. Aggressive

Stage Early vs. advanced disease

Age Performance status Co-morbid conditions

Heart disease, liver disease, renal disease

Management: NHLManagement: NHL

Treatment: Intermediate to High Treatment: Intermediate to High Risk NHLRisk NHL

Treatment: Intermediate to High Treatment: Intermediate to High Risk NHLRisk NHL

Chemotherapy Targeted Agents

Rituximab: Anti-CD20 antibody

Chemotherapy Targeted Agents

Rituximab: Anti-CD20 antibody

Watchful waiting Single agent chemotherapy

Chlorambucil Fludarabine

Combination chemotherapy CVP CHOP

Treatment of Indolent Treatment of Indolent LymphomasLymphomas

International Prognostic Index for International Prognostic Index for NHLNHL

International Prognostic Index for International Prognostic Index for NHLNHL

http://content.nejm.org/content/vol329/issue14/images/large/02t4.jpeg

Early stages, favorable: radiation alone (extended field)

Early stages, unfavorable: moderate amount of chemotherapy (typically four cycles) plus radiation

Advanced stages: extensive chemotherapy (typically eight cycles) with or without consolidating (usually local) radiation

Treatment Strategies: HDTreatment Strategies: HD

Case 2-01-02Case 2-01-02Case 2-01-02Case 2-01-02 92 year old male has no complaints but has been noted to have chronic anemia

for the past 3 years consulted several physicians, given oral iron therapy with apparently some

improvement in hemoglobin levels the maximum reached was 97 gm/L requiring blood transfusions for the past year no changes in his bowel movements, including changes in color no changes in the urine volume or color frequent episodes of cough but no fever weight loss, which was not quantified Physical examination: alert elderly male, wheelchair borne, with VS: BP:

110/70, PR: 100/min, regular, RR: 18/min, regular, Temp: 36.5’C. pale, no jaundice, no lymphadenopathy soft blowing systolic murmur in the left parasternal area, clear breath

sounds no hepatoslenomegaly No pedal edema.

92 year old male has no complaints but has been noted to have chronic anemia for the past 3 years

consulted several physicians, given oral iron therapy with apparently some improvement in hemoglobin levels the maximum reached was 97 gm/L

requiring blood transfusions for the past year no changes in his bowel movements, including changes in color no changes in the urine volume or color frequent episodes of cough but no fever weight loss, which was not quantified Physical examination: alert elderly male, wheelchair borne, with VS: BP:

110/70, PR: 100/min, regular, RR: 18/min, regular, Temp: 36.5’C. pale, no jaundice, no lymphadenopathy soft blowing systolic murmur in the left parasternal area, clear breath

sounds no hepatoslenomegaly No pedal edema.

CBC: HB: 89 gm/L, Hct: 0.26,

WBC: 2.6 x 109/L

segmenters: 39%, lymphocytes: 61%, platelets: 200 x 109/L

CBC: HB: 89 gm/L, Hct: 0.26,

WBC: 2.6 x 109/L

segmenters: 39%, lymphocytes: 61%, platelets: 200 x 109/L



63 year old female had recent onset of dizziness 4 days ago accompanied by headache, palpitations, shortness of breath,

and easy fatigability no fever, cough, orthopnea, PND , nor pedal edema Family history is negative for cancer or blood disease past history of asthma PE: VS: BP: 120/70, PR: 90/min, RR: 20/min, Temp:

37.5’C, pale, no jaundice, no palpable lymph nodes no murmurs, clear breath sounds, no crackles liver not palpable but spleen palpable 3 fingerbreadths

below LSCM.

63 year old female had recent onset of dizziness 4 days ago accompanied by headache, palpitations, shortness of breath,

and easy fatigability no fever, cough, orthopnea, PND , nor pedal edema Family history is negative for cancer or blood disease past history of asthma PE: VS: BP: 120/70, PR: 90/min, RR: 20/min, Temp:

37.5’C, pale, no jaundice, no palpable lymph nodes no murmurs, clear breath sounds, no crackles liver not palpable but spleen palpable 3 fingerbreadths

below LSCM.

CBC: Hb: 71 gm/L Hct: 0.31 WBC : 389 x 109/L

metamyelocytes: 24% bands 21%

segmenters 36% lymphocytes 4%

eosinophils 3 %Platelets: 1689 x 109/L

CBC: Hb: 71 gm/L Hct: 0.31 WBC : 389 x 109/L

metamyelocytes: 24% bands 21%

segmenters 36% lymphocytes 4%

eosinophils 3 %Platelets: 1689 x 109/L


Case 2-02-04Case 2-02-04Case 2-02-04Case 2-02-04 55 year old female noted to have gradual abdominal enlargement

for the past three years with significant increase during the past three months

nonproductive cough for the past three weeks good appetite, no early satiety, weight loss or easy fatigability Physical examination showed VS: BP: 120/70, PR: 84/min, RR:

20/min, Temp: 36.7’C. pink palpebral conjunctivae, no jaundice, no lymphadenopathies no murmurs Lung examination: rhonchi on both lung fields liver was palpable 5 cm below the RSCM, the spleen was palpable

21 cm below the LSCM at MCL no pedal edema

55 year old female noted to have gradual abdominal enlargement for the past three years with significant increase during the past three months

nonproductive cough for the past three weeks good appetite, no early satiety, weight loss or easy fatigability Physical examination showed VS: BP: 120/70, PR: 84/min, RR:

20/min, Temp: 36.7’C. pink palpebral conjunctivae, no jaundice, no lymphadenopathies no murmurs Lung examination: rhonchi on both lung fields liver was palpable 5 cm below the RSCM, the spleen was palpable

21 cm below the LSCM at MCL no pedal edema

CBC showed HB: 158 gm/L, Hct: 0.50, WBC: 23 x 109/L Segmenters 87%, Lymphocytes 11%, Monocytes 2%, Platelets: 474 x 109/L

CBC showed HB: 158 gm/L, Hct: 0.50, WBC: 23 x 109/L Segmenters 87%, Lymphocytes 11%, Monocytes 2%, Platelets: 474 x 109/L


medicine2 - myeloproliferative, lymphoproliferative workshop

Documents