hematologic malignancies failure of terminal differentiation failure of differentiated cells to...

HEMATOLOGIC MALIGNANCIESHEMATOLOGIC MALIGNANCIES

• Failure of terminal differentiation• Failure of differentiated cells to undergo

apoptosis• Failure to control growth• Neoplastic “stem cell”

BIOLOGY

FAILURE OF TERMINAL DIFFERENTIATIONFAILURE OF TERMINAL DIFFERENTIATION

• Result: accumulation of rapidly dividing immature cells

• Example: acute leukemias, aggressive lymphomas

FAILURE TO UNDERGO APOPTOSISFAILURE TO UNDERGO APOPTOSIS

• Result: accumulation of relatively well-differentiated, slow-growing cells

• Example: chronic lymphocytic leukemia, indolent lymphomas

THE NEOPLASTIC STEM CELLTHE 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 DISORDERSMYELOPROLIFERATIVE 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 DISORDERSMYELOPROLIFERATIVE 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 DISORDERSMYELOPROLIFERATIVE 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

SPLENOMEGALY IN MYELOFIBROSIS

Mayo Clin Proc 2004;79:503

JAK2 MUTATION IN CHRONIC JAK2 MUTATION IN CHRONIC MYELOPROLIFERATIVE DISORDERSMYELOPROLIFERATIVE 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 LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA

• 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

BIOLOGY

NEJM 2003;349:1451

NEJM 2003;349:1451

CHRONIC MYELOGENOUS LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA

Blood smear Marrow biopsyBuffy coat

LEUKOSTASIS IN CMLLEUKOSTASIS IN CML

NEJM 2005;353:1044

WBC 300K

CHRONIC MYELOGENOUS LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA

• 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

Natural history

CHRONIC MYELOGENOUS LEUKEMIACHRONIC MYELOGENOUS LEUKEMIA

• Gleevec (imatinib) – inhibits bcr-abl protein kinase• Hydroxyurea• Alfa interferon • Early allogeneic BMT in eligible pts (vs Gleevec Rx?)

TREATMENT

NEJM 2003;349:1399

MYELODYSPLASIAMYELODYSPLASIA

• 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%

MYELODYSPLASIAMYELODYSPLASIA

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)

WHO Classification

SURVIVAL IN MYELODYSPLASIASURVIVAL IN MYELODYSPLASIA

Overall survival Leukemia-free survival

J Clin Oncol 2005;23:7594

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

*

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 SYNDROMEMYELODYSPLASTIC SYNDROME

Myeloblast (red arrow) and abnl RBC precursor (blue arrow)

ACUTE LEUKEMIAACUTE LEUKEMIABiology

• 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 LEUKEMIAACUTE LEUKEMIA

• Bone marrow failure fatigue (anemia) infection (neutropenia) bleeding (thrombocytopenia)

• Tissue infiltration organomegaly skin lesions organ dysfunction pain

Pathophysiology

ACUTE LEUKEMIAACUTE LEUKEMIA

• 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

Pathophysiology (cont)

Hyperleukocytosis in AMLNEJM 2003;349:767

Normal Patient (WBC 250K)

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

ACUTE LEUKEMIAACUTE LEUKEMIA

• Clinical setting• Morphology• Histochemistry• Surface markers• Cytogenetics• Molecular genetics

Information used in classification

ACUTE LEUKEMIAACUTE LEUKEMIA

• Old age, poor performance status• Therapy-induced• Prior myelodysplastic/myeloproliferative disorder• High tumor burden• Cytogenetics: Ph1 chromosome, deletion of 5 or

7, multiple cytogenetic abnormalities

Adverse prognostic features

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 LEUKEMIAACUTE MYELOGENOUS LEUKEMIA

• 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

Epidemiology

ACUTE MYELOGENOUS LEUKEMIASACUTE MYELOGENOUS LEUKEMIAS

• 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)

FAB (French-American-British) classification

Newer classification schemes place more emphasis Newer classification schemes place more emphasis on cytogenetics and less on morphologyon 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 LEUKEMIAACUTE PROMYELOCYTIC LEUKEMIA

• 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

(APML; FAB M3)

M1M0

M2 M3

M5M4

M7M6

Auer rod in AML

ACUTE LYMPHOCYTIC LEUKEMIAACUTE LYMPHOCYTIC LEUKEMIA

• 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)

Classification

L1 ALL L2 ALL L3 ALL

ACUTE LYMPHOCYTIC LEUKEMIAACUTE LYMPHOCYTIC LEUKEMIA

• About 3000 cases/yr in US• 2/3 of cases in children (most common

childhood cancer)• In adults, most cases in elderly

Epidemiology

ACUTE LEUKEMIAACUTE LEUKEMIA

• 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

Treatment

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