Leukemia review:

Leukemia: malignant proliferation of one or more elements of the hematopoietic system à primary BM involvement +/- circulating neoplastic cells in the peripheral blood

•        Acute vs chronic
•      Myeloid vs lymphoid

Leukemia involves neoplastic monoclonal proliferation of hematopoietic progenitor cells = blasts (acute leukemia) or their progeny (chronic leukemia)

-          Monoclonal cells are defined as a group of cells produced from a single ancestral cell by repeated cellular replication

1. Increased proliferation, as a result of:

-          Inability to differentiate and mature → acute leukemia

-          Increased mitosis → acute and chronic leukemia

2. Increased survival of progeny → chronic leukemia

3. Inhibition of normal hematopoietic clones → acute and chronic leukemia

LEADING TO:

·         Overabundance of leukemic cells (“blasts” or mature cells)

·         Deficiency of normal hematopoietic cells

Etiology:

-          Hereditary

-          Chemical: benzene, Alkylating agents

-          Ionizing radiation

-          Congenital (downs) + acquired (9;22 – CML)

-          Virus: HTLV-1

Genetic defects in Leukemia:

-          Activation oncogenes/inactivation TSF

-          Oncogenes which are activated typically encode: GF/GFr/ tyrosine kinases (growth signal transducers), DNA transcription factors

o   9;22 BCR-ABL1: TK à CML

o   15;17 PML-RARa: surface receptor à affects transcription factors  à acute promyelocytic leukemia

Clinical: -          Increase incidence with age (Except ALL = childhood & late adulthood – bimodal peak) -          M>F -          Symptoms: o   Bone pain o   Abdominal discomfort o   Headache o   LAD -          ↓normal blood cells o   Anemia à weakness, fatigue o   Neutropenia à infection/fever o   Thrombocytopenia à bleeding

Physical signs: -          Pallor -          Petechiae/purpura -          Bone tenderness -          Hepatosplenomegaly (HSM) -          LAD -          Gingival infiltrate (AML) -          Skin lesions

Lab findings: -          Aneima/neutropenia/ thrombocytopenia -          Circulating leukemia cells (usually) -          DIC + Coag abnormalitites -          Increased LDH/uric acid §  Typically seen in tumor lysis syndrome post Rx: break down produces of cells – can occur without Rx §  ALL/AML/burkitts – highly associated BM: replacement of normal cells with leukemic cells

	Acute leukemia	Chronic leukemia
Onset	Abrupt	Slow/insidious
Progression	Rapid	Slow, indolent, relentless
Cell	Blasts = immature	Mature cells
Survival	Short (2-3 yrs) Except childhood ALL	Long

	Favorable	unfavorable
AML	8;21 15;17 16q22 breaks	6;9 Inv(3) (3;3) 11q23 breaks 5,7 abn
ALL	Hyperdiploidy 12;21	Hypodiploiidy 9;22 1;19 11q23

Cell markers:

Chronic Myeloproliferative neoplasms:

-          Myelogenous or pluripotent stem cell defects  à overproduction of mostly mature cells

-           Three major non-lymphocytic lineages affected; one predominates

-          Some clinical and morphologic overlap among subtypes, especially in early stages

-          • Some subtypes share a common gene abnormality (JAK2 mutation, affecting tyrosine kinase activity); CML associated with BCR-ABL1, also affecting  tyrosine kinase activity

-           Transformation to acute leukemia

LEUKOCYTE ALKALINE PHOSPHATASE (LAP)  SCORE • 100 peripheral blood neutrophils are scored 0 – 4+ for amount of alkaline phos. • Normal range = 15 – 150 • Decreased in chronic myelogenous leukemia • Normal to increased in leukemoid reaction, polycythemia vera, primary myelofibrosis, etc. LAP increased when there is a left shift = leukemoid reaction!!!!

			Definition		Lab/clinical
CML			Stem cell defect inducing overabundance of granulocytes (predominantly), through . . . • Increased granulocyte proliferation • Premature release of granulocytes from the marrow (and other sites) into the peripheral blood • Prolonged granulocyte lifespan (via inhibition of apoptosis) BCR-ABL1 GENE REARRANGEMENT: • t(9;22)(q34;q11.2) • abnormal tyrosine kinase Rx: Gleevec and second-generation tyrosine kinase inhibitors • Present in all hematopoietic lineages • Identified (cytogenetically and/or genotypically) in 100% of cases of true CML	BCR-ABL1 9;22	CLINICAL FEATURES:Slow, insidious onset SYMPTOMS: General leukemic symptoms, especially abdominal discomfort due to splenomegaly SIGNS: Pallor, petechiae, HSM bone (esp. sternal) tenderness PERIPHERAL BLOOD FINDINGS: • Granulocytosis (WBC up to 250,000), with all stages  of maturation present • Anemia • Thrombocytopenia; thrombocytosis (30%) • Increased LDH, uric acid, vitamin B12 • LAP score decreased Hypercellular (near 100%) BM ACUTE BLAST TRANSFORMATION (“CRISIS”): • If unsuccessfully treated, occurs in nearly all cases,  usually within 1 to 4 years • Often preceded by “accelerated” phase • Definition:  >20% blasts in peripheral blood and/or bone marrow • AML  70% of cases;  ALL 30%
Markedly increased neutrophilic precursors with  progressive maturation, ↑eosinophils and basophils +/- ↑megakaryocytes
Polycythemia vera		Stem cell defect resulting in autonomous erythrocytic cell line, with some overproduction of other hematopoietic cells as well;		JAK2 100%	• LABORATORY FEATURES: - Increased total body RBC mass → increased H - ↓ EPO - Pancellular hematopoietic increase  SYMPTOMS - Hyperviscosity syndrome • SIGNS – -          “Ruddy cyanosis” -          Hepatosplenomegaly -            • COURSE – -          Thromboembolism -           hemorrhage, -          myelofibrosis (“burnt out”), -          acute leukemia (almost always AML) in 5-15% of cases
		Secondary polycythemia Non-neoplastic erythrocytosis secondary to physiologic or abnormal overproduction of erythropoietin			High EPO CAUSES:  -          High altitude -          Cardiopulmonary disease -           Alveolar hypoventilation (“Pickwickian” syndrome) Neoplasms (e.g. renal cell or hepatocellular carcinoma)
Primary myelofibrosis	Stem cell defect inducing increased  hematopoietic (especially abnormal megakaryocytic) Proliferation PATHOGENESIS: Abnormal megakaryocytes produce growth factors (PDGF and TGF-β) that stimulate  fibroblasts (and osteoblasts); causes marrow fibrosis, resulting in extramedullary hematopoiesis			JAK2 50%	• Usual leukemic symptoms and signs • Particularly prominent hepatosplenomegaly due to extensive extramedullary hematopoiesis • Progresses to acute leukemia (almost always AML) in 5-10% of cases
Essential thombocytopenia	Stem cell defect inducing predominantly  megakaryocyte/platelet overproduction			JAK2 40-50%	• Thrombocytosis (often >1,000,000); platelet dysfunction •Thromboembolism and/or bleeding complications • Progression to acute leukemia may occur, but is Uncommon

Myelodysplastic syndromes: MDS Disorder of stem cells: BM does not make enough healthy blood cells

• DEFINITION: Stem cell disorders characterized by abnormal (dysplastic) maturation and enhanced  apoptosis among non-lymphocytic hematopoietic  lineages, leading to ineffective production of blood  cells; may occur de novo or secondary to exposure to  toxins, drugs, or radiation
• PERIPHERAL BLOOD: Various cytopenias
• BONE MARROW:  Dysplastic features in one or more lineages,  ineffective hematopoiesis, maturation arrest in some  subtypes → increased myeloblasts
• CLINICAL COURSE:  May “smolder” for months to years and have complications from cytopenias and many cases ultimately progress to AML (AML with  myelodysplasia-related changes)

CLL: CLL-B/ hairy cell/ chronic leukemia: mature T/NK

	Chronic lymphocytic leukemia B-cell type	Hairy cell
Definition	Neoplastic proliferation of small, immunologically incompetent B lymphocytes with unique immunophenotypic features; biologically identical to small lymphocytic lymphoma, but shows greater bone marrow and peripheral blood involvement at presentation	“Hairy” cells infiltrate mainly bone marrow and spleen; usually with only a small number of leukemic cells in peripheral blood.
Clinical	• Older patients (usually >40 years of age) • Insidious onset, often discovered as incidental finding  on CBC; eventual anemia, thrombocytopenia, splenomegaly, and/or lymphadenopathy	Pancytopenia + splenomegaly
Peripheral blood	Increase in small, mature lymphocytes	Small number hairy cells in blood
BM	Infiltration with similar lymphocytes	Hairy cells infiltrate BM/spleen
Immunophenotyoe	B lymphocytes with expression of CD5 and CD23	Leukemic cells exhibit - - Tartrate-resistent acid phosphatase (TRAP) - Unique immunophenotype “trap the hairy animal”
prognostic	Certain cell markers (eg. CD38 or ZAP-70 expression) and genetic abnormalities associated with more aggressive clinical course	Easily Rx – long survival
transformation	- Prolymphocytic transformation  15 - 30% - Large cell lymphoma (“Richter’s”) 5 - 10% - Acute leukemia very rare