The leukemia

Июль 31, 2022

Содержание

2. TERMINOLOGY A malignant proliferation of monoclonal hematopoetic cells with accumulation of abnormal immature cells which replace
3. Leukemias A very heterogeneic group of disorders, can be classified on a basis of clinical course
4. AML – FAB classification M0 – undifferentiated M1 – early myeloblastic M2 – myelocytic M3 –
5. FAB classification This classification is based mostly on morphology and immunophenotyping of the blasts Has clinical
6. Cytogenetics Cytogenetics is the most important prognostic feature of AML “Favorable” – M2 with t(8;21), M3
7. AML – WHO classification AML with recurrent cytogenetic translocations – M2 with t(8;21), M3 with t(15;17)
8. ALL The FAB classification is not in use Is classified by the phenotype of the blasts
9. ETIOLOGY Environment: irradiation, chemotherapeutic agents, organic solvents – benzene etc. Genetic diseases: neurofibromatosis, Wiscott-Aldrich synd., defective
10. CLINICAL FEAURES AML – 1.2% of all cancer deaths in US (about 9200 new cases per
11. CLINICAL FEATURES The presenting signs are not specific: Anemia – pallor, weakness, dispnoea Neutropenia – fever,
12. LABORATORY Leukocytosis with blasts Metabolic and electrolyte derangement hyperuricemia, hyperkalemia, hyperphosphatemia – tumor lysis syndrome Coagulopathy
13. DIAGNOSIS Blasts in blood or bone marrow smear, Auer rods pathognomonic to AML Immunohistochemistry – peroxidase
14. Immunophenotyping CD – Cluster Designation, molecules on the surface of the cell, characteristic to each cell
15. AML - TREATMENT AML – induction with ARA-C and daunorubicin (7:3); consolidations with HIDAC and others,
16. ALL - TREATMENT Protocols based on treatment of childhood ALL, prolonged and intensive therapy with CNS
17. CML A clonal expansion of hematopoetic progenitors, characterized clinically by myeloid hyperplasia, leukocytosis with basophilia and
18. C M L A phasic disease – chronic phase, accelerated phase, blast crisis Incidence – 1-2:100000
19. CML - cytogenetics The first malignancy in which the link between a chromosomal abnormality and leukemogenesis
21. CML Philadelphia chromosome – a short chromosome 22discovered at 1960 by Novel and Henderford First chromosomal
23. CML pathogenesis The normal product of Abl gene is a protein of 145kd with a week
24. Clinical features Most patients are asymptomatic at diagnosis Splenomegaly ± symptoms, anemia, hepatomegaly, purpura, constitutional symptoms
25. Laboratory Peripheral blood : leukocytosis with “left shift”, basophillia, eeosinophilia, thrombocytosis, anemia Bone marrow: myeloid (M:E>3:1),
26. Laboratory LAP (leukocyte alkaline phosphatase)↓ Transcobalamine↑ Uric acid↑ Cytogenetics - Ph+ {t(9;22)} Molecular - bcr/abl +
27. Accelerated Phase ↑Leukocytosis under treatment ↑Basophilia (>20% basophils and eosinophils >10% blasts in peripheral blood >20%
28. BLAST CRISIS Developes in 75-80% of patients Median time from diagnosis 3-5 years constitutional symptoms, bone
29. TREATMENT Tyrosine kinase inhibitors - glyvec (imatinib mesylate), nilotinib, dasatinib etc., major cytogenetic and molecular responses
30. C L L A progressive accumulation of functionally incompetent mature lymphocytes 15-20% of all leukemias, M:F=1.7:1
31. C L L Frequent family history of CLL, other B-cell malignancies, autoimmune disorders No other risk
32. C L L Immunophenotyping: B-cell markers CD19, CD20, CD21, CD23, ; T-cell marker CD5 is a
33. Clinical Manifestations Autoimmune features - Coomb’s+ hemolytic anemia, ITP Recurrent infections - due to hypogammaglobulinemia Symptoms:
34. Laboratory Findings >5000 mature appearing lymphocytes Anemia, thrombocytopenia Bone marrow - infiltration by same lymphocytes, decrease
35. Diagnostic Criteria Absolute lymphocytosis >5000/ml on few consecutive tests At least 30% lymphocytes in normo- or
36. CLL - Staging - Rai System Stage 0 - lymphocytosis blood,marrow Stage 1 - lymphocytosis +
37. CLL - Staging Binet Stage A - lymphocytosis and two or less areas of enlarged lymph
38. CLL -Treatment Rai st. 0-2 or Binet st. A-B ⇒ observe every 3-6 months, treat if
39. Treatment Options Chemotherapy - steroids, alkylating agents ± steroids, purine analogues - fludarabine, combinations Monoclonal antibodies
40. CLL - Prognosis Extremely variable - some have progressive course and die within 2-3 years, some
41. Richter’s Syndrome In 3-5% the disease undergoes a transformation into aggressive lymphoma - diffuse large cell
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TERMINOLOGY
A malignant proliferation of monoclonal hematopoetic cells with accumulation of abnormal

immature cells which replace a normal bone marrow.
Those cells retain the capacity to divide and proliferate, but lose the ability to differentiate terminally into mature hematopoetic cells and to die in a programmed cell death (apoptosis)

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Leukemias
A very heterogeneic group of disorders, can be classified on a

basis of clinical course as acute or chronic, on a basis of cell lineage – myelogenous or lymphatic
AML – Acute Myeloblastic Leukemia
ALL – Acute Lymphoblastic Leukemia
CML – Chronic Myeloid Leukemia
CLL – Chronic Lymphocytic Leukemia

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AML – FAB classification
M0 – undifferentiated
M1 – early myeloblastic
M2 – myelocytic
M3

– promyelocytic
M4 – myelomonocytic
M5 – monocytic/monoblastic
M6 – erythroid
M7 - megacariocytic

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FAB classification
This classification is based mostly on morphology and immunophenotyping of

the blasts
Has clinical and prognostic correlation, but not consistent
Updates should include cytogenetic features

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Cytogenetics
Cytogenetics is the most important prognostic feature of AML
“Favorable” –

M2 with t(8;21), M3 with t(15;17), M4eo with (inv 16)
Regular – normal caryotype
Unfavorable 11q23, 7q-, 5q-, trisomy 8, FLT-3 polymorphism, etc.

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AML – WHO classification
AML with recurrent cytogenetic translocations – M2 with

t(8;21), M3 with t(15;17) and variants, M4eo with (inv16), AML with 11q23 abnormalities
AML with multilineage dysplasia ± MDS
AML or MDS therapy related (alkylating agents, epydiphylotoxin, other)
FAB subtypes without other features
Acute biphenotypic leukemia

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ALL
The FAB classification is not in use
Is classified by the phenotype

of the blasts – early B-lymphoblastic, T-lymphoblastic, mature B-lymphoblastic (Burkitt leukemia)
“Favorable” cytogenetics – t(12;21) in children
Unfavorable – Ph chromosome t(9;22), 11q23, t(4;11)

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ETIOLOGY
Environment: irradiation, chemotherapeutic agents, organic solvents – benzene etc.
Genetic diseases:

neurofibromatosis, Wiscott-Aldrich synd., defective DNA repair – Fanconi, Down synd.
Acquired disorders: Aplastic Anemia, PNH
MOST OF THE CASES APPEAR WITH NO APPARENT RISK FACTORS!!!

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CLINICAL FEAURES
AML – 1.2% of all cancer deaths in US (about

9200 new cases per year), the incidence increases with age. In adults represents 90% of acute leukemias
ALL less prevalent in adults, the incidence increases in seventh and eighth decades of age

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CLINICAL FEATURES
The presenting signs are not specific:
Anemia – pallor, weakness, dispnoea
Neutropenia

– fever, infections
Thombocytopenia – bleeding, petechiae
Extramedullary - mild splenomegaly, skin involvement – leukemia cutis, chloromas, gingival hyperplasia more in monocytic or M2 with t(8;21), CNS more in ALL

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LABORATORY
Leukocytosis with blasts
Metabolic and electrolyte derangement hyperuricemia, hyperkalemia, hyperphosphatemia – tumor

lysis syndrome
Coagulopathy – DIC typical to APL

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DIAGNOSIS
Blasts in blood or bone marrow smear, Auer rods pathognomonic to

AML
Immunohistochemistry – peroxidase (AML), non specific esterase (monocytic), PAS (lymphoid, erytroid), acid phosphatase (lymphoid, erythroid, megacariocytic)

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Immunophenotyping
CD – Cluster Designation, molecules on the surface of the cell,

characteristic to each cell type, identified by monoclonal Ab.
CD33, CD34, CD11, CD13, CD14 – myeloid
CD41, CD61 – megakaryocytic
Glycophorin A – erythroid
CD2, CD3, CD4, CD7, CD8 – T lymphocytes
CD10, CD19, CD20, CD22 – B lymphocytes

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AML - TREATMENT
AML – induction with ARA-C and daunorubicin (7:3); consolidations

with HIDAC and others, autologous HSCT, allogeneic HSCT, monoclonal Ab – conjugated anti-CD33 (Gemtuzumab Ozogamycine)
APL – ATRA, chemotherapy, Arsenic

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ALL - TREATMENT
Protocols based on treatment of childhood ALL, prolonged and

intensive therapy with CNS prophylaxis and maintenance
Autologous HSCT
Allogeneic HSCT

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CML
A clonal expansion of hematopoetic progenitors, characterized clinically by myeloid hyperplasia,

leukocytosis with basophilia and splenomegaly

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C M L
A phasic disease – chronic phase, accelerated phase, blast

crisis
Incidence – 1-2:100000
15-20% of leukemias in adults
Median age at diagnosis – 65 years
↑incidence in survivors of atomic bomb in Hiroshima and Nagasaki, atomic accident in Chernobyl

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CML - cytogenetics
The first malignancy in which the link between a

chromosomal abnormality and leukemogenesis was established
The Philadelphia chromosome – an abnormally short chromosome 22
The t(9;22) results from translocation of c-abl gene from chromosome 9 to bcr gene on chromosome 22, the new fusion gene – bcr/abl encodes a chimeric protein with strong unregulated tyrosine kinase activity

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CML
Philadelphia chromosome – a short chromosome 22discovered at 1960 by Novel

and Henderford
First chromosomal Abnormality connected to malignancy
Caused by translocation t(9;22)(q34;q11)
Results in oncogen bcr/Abl that codes for a protein an unregulated Tyrosine Kinase

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CML pathogenesis
The normal product of Abl gene is a protein of

145kd with a week tyrosine kinase activity, strictly regulated and important in cell cycle regulation
The bcr/Abl product is 190,210 or 230kd protein with strong and autonomous TK activity, can causecell proliferation and malignant transformation and inhibit apoptosis. It’s substrate is oncogen ras which inhibits tumor suppressor gene p-53

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Clinical features
Most patients are asymptomatic at diagnosis
Splenomegaly ± symptoms, anemia, hepatomegaly,

purpura, constitutional symptoms – fatigue, anorexia, weight loss,sweats,low grade fever, hyperleukocytosis,bone pain (rare in chronic phase), priapism

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Laboratory
Peripheral blood : leukocytosis with “left shift”, basophillia, eeosinophilia, thrombocytosis,

anemia

Bone marrow: myeloid (M:E>3:1), blasts <10%, no dysplasia, abundant megacaryocytes, fibrosis, monocytes<3%

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Laboratory
LAP (leukocyte alkaline phosphatase)↓
Transcobalamine↑
Uric acid↑
Cytogenetics - Ph+ {t(9;22)}
Molecular - bcr/abl +
Gene

expression pattern (experimental)

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Accelerated Phase
↑Leukocytosis under treatment
↑Basophilia (>20% basophils and eosinophils
>10% blasts in peripheral

blood
>20% blasts + promyelocytes in marrow
Thrombocytosis
Additional chromosomal abnormalities

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BLAST CRISIS
Developes in 75-80% of patients
Median time from diagnosis 3-5 years
constitutional

symptoms, bone pain, extramedullary (skin, lymph nodes, CNS)
>30% blasts in bone marrow
Additional chromosomal abnormalities
50% - myeloid, 25% - lymphoid, 25% - biphenotypic

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TREATMENT
Tyrosine kinase inhibitors - glyvec (imatinib mesylate), nilotinib, dasatinib etc., major

cytogenetic and molecular responses in over 80%, changed a natural history of the disease
Chemotherapy – hydrea, busulphan, ARA-C
α-Interferon - 15% cytogenetic response with prolonged survival
Allogeneic bone marrow transplant, 45-70% long term survival, curative. In TKI`s resistant or intolerant cases.

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C L L
A progressive accumulation of functionally incompetent mature lymphocytes
15-20% of

all leukemias, M:F=1.7:1
>95% B-CLL; 2-5% T-CLL
In people > 70, incidence 20/100000, median age at diagnosis 55

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C L L
Frequent family history of CLL, other B-cell malignancies, autoimmune

disorders
No other risk factors
The cells overexpress bcl-2, an antiapoptotic gene, lack of apoptosis

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C L L
Immunophenotyping: B-cell markers CD19, CD20, CD21, CD23, ; T-cell

marker CD5 is a characteristic finding.
ZAP-70, IgVH mutational status
Chromosomal abnormalities found by FISH in 60%, most frequent chr. 13, 12, 11, 17(p53)
Chr. 13 – good prognosis, chr. 11, 12, 17 – bad prognosis, chemotherapy resistance, short remissions, short survival

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Clinical Manifestations
Autoimmune features - Coomb’s+ hemolytic anemia, ITP
Recurrent infections - due

to hypogammaglobulinemia
Symptoms: weakness, weight loss, night sweats, fever
Physical examination: lymphadenopathy, hepatomegaly, splenomegaly

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Laboratory Findings
>5000 mature appearing lymphocytes
Anemia, thrombocytopenia
Bone marrow - infiltration

by same lymphocytes, decrease in myeloid and erythroid precursors, (if ITP or AIHA - abundant megakariocytes and erythroid lineage
“Smudged cells” - Gumprecht cells

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Diagnostic Criteria
Absolute lymphocytosis >5000/ml on few consecutive tests
At least 30% lymphocytes

in normo- or hypercellular marrow
Monoclonal B-cell phenotype, CD5+

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CLL - Staging - Rai System
Stage 0 - lymphocytosis blood,marrow
Stage 1

- lymphocytosis + lymph nodes
Stage 2 - St.0-1 + enlarged liver or spleen
Stage 3 - all above + anemia
Stage 4 - all above + thrombopenia

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CLL - Staging Binet
Stage A - lymphocytosis and two or less

areas of enlarged lymph nodes
Stage B - as A with three or more areas of lymph node enlargement
Stage C - as A or B with anemia or thrombocytopenia

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CLL -Treatment
Rai st. 0-2 or Binet st. A-B ⇒ observe every

3-6 months, treat if disease progress, short doubling time, symptomatic, recurrent infections, ITP, AIHA
Advanced stage, symptomatic needs treatment at diagnosis

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Treatment Options
Chemotherapy - steroids, alkylating agents ± steroids, purine analogues -

fludarabine, combinations
Monoclonal antibodies - anti CD20 (Rituximab), anti CD52 (Campath 1H) ± chemotherapy, anti CD23
High dose therapy with hematopoetic stem cell transplantation - autologous, allogeneic, low intensity (“mini-transplant”)

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CLL - Prognosis
Extremely variable - some have progressive course and die

within 2-3 years, some have indolent disease with 10-20 years survival
The prognostic factors are - stage at diagnosis, cytogenetics, molecular – mutation status, ZAP-70, CD38 expression; morphology – diffuse bone marrow infiltration, large cells (prolymphocytes), T-lineage, B-symptoms, high LDH, short doubling time

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Richter’s Syndrome
In 3-5% the disease undergoes a transformation into aggressive lymphoma

- diffuse large cell or immunoblastic
Severe B-symptoms, increased LDH, lymphadenopathy
The prognosis is poore, median survival <6 months

The leukemia

Содержание

TERMINOLOGYA malignant proliferation of monoclonal hematopoetic cells with accumulation of abnormal

LeukemiasA very heterogeneic group of disorders, can be classified on a

AML – FAB classification M0 – undifferentiatedM1 – early myeloblasticM2 – myelocyticM3

FAB classificationThis classification is based mostly on morphology and immunophenotyping of

CytogeneticsCytogenetics is the most important prognostic feature of AML “Favorable” –

AML – WHO classificationAML with recurrent cytogenetic translocations – M2 with

ALLThe FAB classification is not in useIs classified by the phenotype

ETIOLOGY Environment: irradiation, chemotherapeutic agents, organic solvents – benzene etc.Genetic diseases:

CLINICAL FEAURESAML – 1.2% of all cancer deaths in US (about

CLINICAL FEATURESThe presenting signs are not specific:Anemia – pallor, weakness, dispnoeaNeutropenia

LABORATORYLeukocytosis with blastsMetabolic and electrolyte derangement hyperuricemia, hyperkalemia, hyperphosphatemia – tumor

DIAGNOSISBlasts in blood or bone marrow smear, Auer rods pathognomonic to

ImmunophenotypingCD – Cluster Designation, molecules on the surface of the cell,

AML - TREATMENTAML – induction with ARA-C and daunorubicin (7:3); consolidations

ALL - TREATMENTProtocols based on treatment of childhood ALL, prolonged and

CMLA clonal expansion of hematopoetic progenitors, characterized clinically by myeloid hyperplasia,

C M LA phasic disease – chronic phase, accelerated phase, blast

CML - cytogeneticsThe first malignancy in which the link between a

CMLPhiladelphia chromosome – a short chromosome 22discovered at 1960 by Novel

CML pathogenesisThe normal product of Abl gene is a protein of

Clinical featuresMost patients are asymptomatic at diagnosisSplenomegaly ± symptoms, anemia, hepatomegaly,

Laboratory Peripheral blood : leukocytosis with “left shift”, basophillia, eeosinophilia, thrombocytosis,

LaboratoryLAP (leukocyte alkaline phosphatase)↓Transcobalamine↑Uric acid↑Cytogenetics - Ph+ {t(9;22)}Molecular - bcr/abl +Gene

Accelerated Phase↑Leukocytosis under treatment↑Basophilia (>20% basophils and eosinophils>10% blasts in peripheral

BLAST CRISISDevelopes in 75-80% of patientsMedian time from diagnosis 3-5 yearsconstitutional

TREATMENTTyrosine kinase inhibitors - glyvec (imatinib mesylate), nilotinib, dasatinib etc., major

C L LA progressive accumulation of functionally incompetent mature lymphocytes15-20% of

C L LFrequent family history of CLL, other B-cell malignancies, autoimmune

C L LImmunophenotyping: B-cell markers CD19, CD20, CD21, CD23, ; T-cell

Clinical ManifestationsAutoimmune features - Coomb’s+ hemolytic anemia, ITPRecurrent infections - due

Laboratory Findings >5000 mature appearing lymphocytesAnemia, thrombocytopenia Bone marrow - infiltration

Diagnostic CriteriaAbsolute lymphocytosis >5000/ml on few consecutive testsAt least 30% lymphocytes

CLL - Staging - Rai SystemStage 0 - lymphocytosis blood,marrowStage 1

CLL - Staging BinetStage A - lymphocytosis and two or less

CLL -TreatmentRai st. 0-2 or Binet st. A-B ⇒ observe every

Treatment OptionsChemotherapy - steroids, alkylating agents ± steroids, purine analogues -

CLL - PrognosisExtremely variable - some have progressive course and die

Richter’s SyndromeIn 3-5% the disease undergoes a transformation into aggressive lymphoma

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