Overview of hematologic malignancies

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HEMATOLOGIC MALIGNANCIES

BIOLOGY

Failure of terminal differentiation

Failure of differentiated cells to undergo apoptosis

Failure to control growth

Neoplastic “stem cell”

FAILURE OF TERMINAL DIFFERENTIATION

Result: accumulation of rapidly dividing immature cells

Example: acute leukemias, aggressive lymphomas

FAILURE TO UNDERGO APOPTOSIS

Result: accumulation of relatively welldifferentiated, slow-growing cells

Example: chronic lymphocytic leukemia, indolent lymphomas

THE NEOPLASTIC STEM CELL

Propagation of malignant clone may depend on a subset of cells with stem cell-like properties

Some neoplastic stem cells retain the ability to differentiate into more than one cell type (eg, myeloproliferative/myelodysplastic disorders)

Eradication of neoplastic stem cell essential to cure disease?

Neoplastic stem cells may be slow-growing and resistant to treatment

Blood 2006;107:265

MYELOID NEOPLASIA

Myeloproliferative disorders

Polycythemia vera

Essential thrombocytosis

Myelofibrosis/myeloid metaplasia

Chronic myelogenous leukemia

Myelodysplasia

Acute myelogenous leukemia

MYELOPROLIFERATIVE DISORDERS

Affected cell: myeloid stem cell

All three cell lines affected; clonal hematopoiesis in most cases

Differentiation: normal to mildly abnormal

Kinetics: effective hematopoiesis

Marrow: hypercellular, variably increased reticulin fibrosis

Peripheral blood: increase in one or more cell lines in most cases

Exception: myelofibrosis

MYELOPROLIFERATIVE DISORDERS

Polycythemia Vera

Essential Thrombocythemia

Myelofibrosis/Myeloid Metaplasia

Chronic Myelogenous Leukemia

Polycythemia vera Essential thrombocythemia

Myeloid metaplasia CML

MARROW FIBROSIS

H&E Reticulin stain

MYELOPROLIFERATIVE DISORDERS

Diagnosis usually determined by peripheral blood counts

High Hct or platelet count may cause vaso-

• occlusive symptoms

Risk of portal vein thrombosis

Splenomegaly, constitutional symptoms frequent

Phlebotomy to control high Hct, hydroxyurea or other myelosuppressive Rx to control platelets, constitutional sx, etc

Transition to myelofibrosis or acute leukemia possible

VASO-OCCUSION IN POLYCYTHEMIA VERA

NEJM 2004; 350:99

NEJM 2004; 350:99

Mayo Clin Proc 2004;79:503

SPLENOMEGALY IN MYELOFIBROSIS

JAK2 MUTATION IN CHRONIC

MYELOPROLIFERATIVE DISORDERS

• Activation of JAK2 tyrosine kinase by cytokines initiates an important signaling pathway in myeloid cells

• A single point mutation of JAK2 (Val617Phe) has been identified in a high proportion (65-95%) of patients with polycythemia vera, and also in a substantial proportion of cases of essential thrombocytosis and myelofibrosis

• This mutation markedly increases the sensitivity of the cells to the effects of erythropoietin and other cytokine growth factors

• Testing for this mutation represents an important diagnostic tool

• This finding may lead to development new targeted therapies for myeloproliferative disorders

Mayo Clin Proc 2005;80:947

Diagnostic algorithm for polycythemia vera

Mayo Clin Proc 2005;80:947

CHRONIC MYELOGENOUS LEUKEMIA

BIOLOGY

Virtually all cases have t(9;22) (Ph1 chromosome) or variant translocation involving same genes

• bcr gene on chromosome 22 fused with abl gene on 9

Fusion gene encodes active tyrosine kinase

Clonal expansion of all myeloid cell lines

NEJM 2003;349:1451

NEJM 2003;349:1451

CHRONIC MYELOGENOUS LEUKEMIA

Blood smear Buffy coat Marrow biopsy

LEUKOSTASIS IN CML

NEJM 2005;353:1044

WBC 300K

CHRONIC MYELOGENOUS LEUKEMIA

Natural history

Incidence 1:100,000/yr

Peak incidence in 40s and 50s

Leukocytosis with mixture of mature and immature forms

Thrombocytosis common

Splenomegaly, constitutional symptoms, eventual leukostasis

Transition to acute leukemia (blast crisis) in 20%/yr

 blasts may be myeloid or lymphoid essentially 100% mortality without BMT

CHRONIC MYELOGENOUS LEUKEMIA

TREATMENT

Gleevec (imatinib) – inhibits bcr-abl protein

• kinase

Hydroxyurea

Alfa interferon

Early allogeneic BMT in eligible pts (vs Gleevec

Rx?)

NEJM 2003;349:1399

MYELODYSPLASIA

Affected cell: myeloid stem cell

All cell lines affected, clonal hematopoiesis

Differentiation: mildly to severely abnormal

Morphology and function may be affected

Kinetics: Ineffective hematopoiesis (apoptosis of

• maturing cells in marrow)

Marrow: variable cellularity

Peripheral blood: decrease in one or more cell lines

(usually anemia with or without other cytopenias)

Platelets and WBC occasionally increased

Cytogenetic abnormalities frequent

Risk of transition to acute leukemia high when marrow blast count > 5%

MYELODYSPLASIA

WHO Classification

Myelodysplastic disorders

Refractory anemia

Refractory anemia with ringed sideroblasts

Refractory cytopenia with multilineage dysplasia

Refractory anemia with excess blasts-1 (5-10% blasts)

RAEB-2 (10-20% blasts)

Mixed myeloproliferative/myelodysplastic disorders

Chronic myelomonocytic leukemia

Atypical CML (bcr-abl negative)

SURVIVAL IN MYELODYSPLASIA

*

Overall survival Leukemia-free survival

*

Mortality of low-risk (RA) patients >70 no different from general population

J Clin Oncol 2005;23:7594

Myelodysplasia: blood smear

Myelodysplasia: blood smears with abnormal neutrophils

Myelodysplasia: marrows showing dyserythropoeisis and hypolobulated megakaryocyte

Myelodysplasia: acquired  -thalassemia with Hgb H inclusions in

RBC. This is caused by somatic mutations in the  -globin gene or an associated regulatory gene, limited to the neoplastic clone

Blood 2005;105:443

MDS: micromegakarycyte MDS: hypercellular marrow

MDS: ringed sideroblast CMML

RAEB – marrow blasts

RAEB – circulating blast, agranular PMN

MYELODYSPLASTIC SYNDROME

Myeloblast (red arrow) and abnl

RBC precursor (blue arrow)

ACUTE LEUKEMIA

Biology

• Leukemic clone: cells unable to terminally differentiate

– May be lymphoid or myeloid

– AML: May arise from abnormal stem cell

(eg in MDS/MPD) or de novo

• Accumulation of immature cells (blasts)

• Marrow replaced by leukemic cells

• Blasts accumulate in blood and other organs

ACUTE LEUKEMIA

Pathophysiology

Bone marrow failure

 fatigue (anemia)

 infection (neutropenia) bleeding (thrombocytopenia)

Tissue infiltration

 organomegaly

 skin lesions organ dysfunction pain

ACUTE LEUKEMIA

Pathophysiology (cont)

Leukostasis (WBC > 50-100K)

 retinopathy

 encephalopathy/CNS bleeding pneumonopathy

Biochemical effects of leukemic cell products

 hyperuricemia/tumor lysis syndrome

DIC renal tubular dysfunction (lysozymuria)

 lactic acidosis hypercalcemia (rare) spurious hypoglycemia/hypoxemia/hyperkalemia

Hyperleukocytosis in AML

NEJM 2003;349:767

Normal Patient

(WBC 250K)

26 yo with fever, encephalopathy, retinopathy, dyspnea, lymphadenopathy

ACUTE LEUKEMIA

Information used in classification

Clinical setting

Morphology

Histochemistry

Surface markers

Cytogenetics

Molecular genetics

ACUTE LEUKEMIA

Adverse prognostic features

Old age, poor performance status

Therapy-induced

Prior myelodysplastic/myeloproliferative

• disorder

High tumor burden

Cytogenetics: Ph 1 chromosome, deletion of 5 or

7, multiple cytogenetic abnormalities

ACUTE MYELOGENOUS LEUKEMIA

Affected cell: myeloid stem cell or committed progenitor cell

Differentiation: arrested at early stage, with absent or decreased maturation

Kinetics: marrow replacement by immature cells, decreased normal hematopoiesis

Marrow: usually markedly hyercellular with preponderance of blast forms

Hypocellular variants known

Peripheral blood: variable decrease in all cell lines with or without circulating immature cells

ACUTE MYELOGENOUS LEUKEMIA

Epidemiology

90% of adult acute leukemia: 2.2 deaths/100,000/yr

Incidence rises with age

Risk factors: exposure to ionizing radiation, alkylating agents and other mutagens (implicated in10-15% of all cases), certain organic solvents (benzene)

Precursor diseases: myelodysplastic & myeloproliferative disorders, myeloma, aplastic anemia, Down syndrome,

Klinefelter syndrome, Fanconi syndrome, Bloom syndrome

ACUTE MYELOGENOUS LEUKEMIAS

FAB (French-American-British) classification

M0 (minimal differentiation)

M1 (myeloid blasts)

M2 (some differentiation)

M3 (promyelocytic)

M4 (myelomonocytic)

M5 (monocytic)

M6 (erythroleukemia)

M7 (megakaryoblastic leukemia)

Unclassifiable (evolved from MDS, other secondary leukemias)

Newer classification schemes place more emphasis on cytogenetics and less on morphology

WHO classification of AML

• AML with recurrent cytogenetic abnormalities

– t(8;21)

– inv(16)

– Acute promyelocytic leukemia – t(15;17) and variants

– AML with 11q23 (MLL gene) abnormalities

• AML with multilineage dysplasia

AML/MDS, therapy-related

• AML not otherwise categorized

– Minimally differentiated

– Without maturation

– With maturation

– Acute myelomonocytic leukemia

– Acute monoblastic and monocytic leukemia

– Acute erythroid leukemia

– Acute megakaryblastic leukemia

– Acute basophilic leukemia

– Acute panmyelosis with myelofibrosis

– Myeloid sarcoma

• AML with ambiguous lineage

– Undifferentiated AML

– Bilineal AML

– Biphenotypic AML

ACUTE PROMYELOCYTIC LEUKEMIA

(APML; FAB M3)

• t (15;17)

Translocation involves retinoic acid

• receptor gene

High incidence of DIC/fibrinolysis

All-trans retinoic acid induces remission in high proportion of cases

Favorable prognosis

M0 M1

M2 M3

M4 M5

M6 M7

Auer rod in AML

ACUTE LYMPHOCYTIC LEUKEMIA

Classification

Morphology (FAB)

L1 (uniform)

L2 (pleomorphic)

L3 (Burkitt-type)

Immunophenotypic

B-cell (Burkitt-type, 2-3% of cases)

Pre-B cell (80% )

T-lineage

Mixed lineage (lymphoid-myeloid)

L1 ALL L2 ALL L3 ALL

ACUTE LYMPHOCYTIC LEUKEMIA

Epidemiology

About 3000 cases/yr in US

2/3 of cases in children (most common childhood cancer)

In adults, most cases in elderly

ACUTE LEUKEMIA

Treatment

Remission induction: aggressive combination chemotherapy

Post-remission

AML: consolidation (high-dose) or auto-BMT

ALL: consolidation, then maintenance (lower dose)

Allogeneic bone marrow transplant in selected patients

Cure rates 75%+ in childhood ALL; as high as 50% in "good risk" adults, up to 60% in BMT recipients

Overall cure rates still low in adults

SURVIVAL ACCORDING TO AGE IN PATIENTS WITH

FAVORABLE CYTOGENETICS TREATED FOR AML

(Excluding APML)

Blood 2006;107:3481

SURVIVAL ACCORDING TO AGE IN PATIENTS WITH

INTERMEDIATE CYTOGENETICS TREATED FOR AML

Blood 2006;107:3481

SURVIVAL ACCORDING TO AGE IN PATIENTS WITH

UNFAVORABLE CYTOGENETICS TREATED FOR AML

Blood 2006;107:3481

EFFECT OF AGE AND PERFORMANCE STATUS ON

EARLY MORTALITY IN TREATED AML

Blood 2006;107:3481

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