Acute Leukemia Dr. Noha Noufal

Objectives To understand the general aspects of leukemia including definition, common feature and general classification and the basic diagnostic tool for acute leukemia To understand the general concepts of leukemia pathogenesis To understand the difference between T-ALL and B-ALL in term of clinical and pathological features To understand the clinical features of acute lymphoblastic leukemia and recognize the most important prognostic factors. To understand the clinical presentation and recognize the importance of early diagnosis of acute myeloid leukemia and their significance in therapeutic approaches To know the most important indicators implicated in prognosis of acute myeloid leukemia.

Neoplastic Proliferation of White Blood Cells Based on the origin and differentiation of tumor cells Lymphoid Neoplasms Leukemia Hodgkin Lymphoma Non Hodgkin Lymphoma Myeloid Neoplasm Myelodysplastic syndrome Myeloproliferative syndrome

Introduction: Definition: The word Leukemia comes from the Greek leukos which means "white" and aima which means "blood". The leukaemias are a group of disorders characterized by the accumulation of malignant white cells in the bone marrow and blood. Leukemias cause symptoms because of: 1- Bone marrow failure (e.g. anaemia, neutropenia, thrombocytopenia);and 2- Infiltration of organs (e.g. liver, spleen, lymph nodes, meninges, brain, skin or testes).

Classification of leukaemia: The main classification is into four types: Acute : Acute Lymphoblastic Leukemia (ALL) Acute Myeloid Leukemia (AML) Chronic : Chronic Lymphoid Leukemia (CLL) Chronic Myeloid Leukemia (CML)

Myeloid vs Lymphoid Any disease that arises from the myeloid elements (white cell, red cell, platelets) is a myeloid disease ….. AML, CML Any disease that arises from the lymphoid elements is a lymphoid disease ….. ALL, CLL

Acute vs. chronic leukemia Acute leukemias: Young, immature, blast cells in the bone marrow (and often blood) More fulminant presentation More aggressive course Chronic leukemias: Accumulation of mature, differentiated cells Often subclinical or incidental presentation In general, more indolent (slow) course Frequently splenomegaly Mature appearing cells in the B.M and blood 4/26/2019

Leukemia Vs. Lymphoma Leukemia Malignancy of hematopoietic cells Starts in bone marrow, can spread to blood, nodes Myeloid or lymphoid Acute or chronic Lymphoma Starts in lymph nodes, can spread to blood, marrow Lymphoid only Hodgkin or non-Hodgkin

Etiology of Acute Leukemia: Combination of predisposing factors including genetic and environmental influences. Chronic exposure to chemical such as benzene Smoking (increase the risk 1.3- 2 fold in smokers) Radiation exposure. Cytotoxic therapy of breast, lung and testicular cancer. Congenital anomaly. The presence of primary immunodeficiency and infection with the human T –cell leukemia virus type-1 HTLV-1 & EBV)

How to Diagnose Leukemia Clinical setting CBC Bone Marrow aspiration Morphology Immunophenotyping Molecular studies Cytogenetics

ACUTE LYMPHOBLASTIC LEUKEMIAS (ALL)

Development of Lymphocytes

Classification of Acute lymphoid Leukemia WHO Classified Lymphoid Neoplasms according to cell of origin into neoplasms derived from T- cell Lineage and those develop from B- cell Lineage: Precursor B and T cell lymphoblastic lymphoma/ leukemia—commonly called acute lymphoblastic leukemia (ALL). Acute lymphoblastic leukaemia (ALL) is caused by an accumulation of lymphoblasts in the bone marrow either immature B (pre- B) which called (B- ALL) or immature T (pre- T) which called (T- ALL).

Incidence of ALL Most common malignancy of childhood. The incidence of B- ALL is highest at 3–7 years, with 75% of cases occurring before the age of 6. There is a secondary rise after the age of 40 years. 85% of cases are of B-cell lineage (B- ALL) and have an equal sex incidence. There is a male predominance for the 15% of T-cell ALL (T-ALL), and occurs in adolescents.

Pathogenesis Many chromosomal aberrations seen in ALL dysregulate the expression and function of transcription factors that are required for the normal differentiation of B and T cell progenitors lead to maturation arrest and increased self-renewal and decreased apoptosis. Multiple Mutations are required to produce full prone to ALL. B-ALLs has loss-of-function mutations in genes that are required for B cell differentiation, such as PAX5. Up to 70% of T-ALLs have gain-of function mutations in NOTCH1, a gene that is essential for T cell differentiation

Morphology, and immunophenotyping of ALL Morphology, and immunophenotyping of ALL. - Lymphoblasts are large and heterogenous show scanty cytoplasm without granules. Sometimes vacuolated cytoplasm is noticed. - Acute lymphoblastic leukaemia: bone marrow cells staining positive for TdT by immunoperoxidase, B- ALL: CD 19 positive T- ALL: CD3 positive a b c d

Clinical features: Clinical features are a result of the following: Bone marrow failure Anaemia Neutropenia (increased liability to infections) Thrombocytopenia (spontaneous bruises, purpura, bleeding gums and menorrhagia. Organ infiltration This causes tender bones, lymphadenopathy, moderate splenomegaly, hepatomegaly and meningeal syndrome (headache, nausea and vomiting, blurring of vision & diplopia).

Investigations Haematological investigations reveal a normochromic normocytic anaemia with thrombocytopenia in most cases. Total WBC may be ↓,↔, or ↑ to 200 × 109/L or more. The blood film typically shows a variable numbers of blast cells. The bone marrow is hypercellular with >20% leukaemic blasts.

Differences Between B-ALL &T-ALL Markers B cell T cell CD10, CD19, CD79a CD3 Percentage 85% 15% Age Children (3 years) Adolescent, males Clinical ------- Mediastinal mass WBC count Less Higher Prognosis Better Worse Mutant genes PAX5 NOTCH1 Cytogenetic Hyperdiploidy & t (12;21)ETV, RUNX gene and t (9;22) ABL, BCR PTEN & CDKN2A mutations

Treatment: Chemotherapy (high cure rate. Stem cell transplantation Overall, >85% of children can now expect to be cured. The cure rate in adults drops significantly to less than 5% over the age of 70 years.

ACUTE MYELOID LECUKEMIA (AML)

Acute Myeloid Leukemia Incidence: AML primarily affects older adults; the median age is 50 years. It forms only a minor fraction (10–15%) of the leukaemias in childhood Classification (of prognostic significance): (1) AMLs associated with specific genetic aberrations. (2) AMLs with dysplasia, many of which arise from MDS. (3) AMLs occurring after genotoxic chemotherapy. (4) AMLs Not Otherwise Classified.

Pathogenesis of Acute Myeloid Leukemia (AML) Most AMLs harbor mutations in genes encoding transcription factors that are required for normal myeloid cell differentiation lead to accumulation of immature myeloid cells (blasts) in the marrow and replace normal elements . Abnormal immature leukocytes then circulates in the blood and infiltrate the blood forming organs ( liver, spleen, lymph nodes) and other sites throughout the body Cytogenetic: t(15;17), the chimeric gene produces a PML/RARA fusion protein that blocks myeloid differentiation at the promyelocytic stage. This lead to abnormal blasts accumulation in bone marrow.

Morphology MORE than 20% of BLASTS are needed in the marrow for a diagnosis of acute myeloid leukemia!!! (i.e., ANY kind of BLAST myeloblasts, monoblasts, erythroblasts, or megakaryoblasts ) Immunohistochemistry: Most tumors express some combination of myeloid-associated antigens, such as CD34, CD13, CD14, CD15, CD64, or CD117 (KIT).

Auer Rods: red staining rod like structures which is specific for neoplastic myeloblasts

Clinical features: Related to problems caused by: Bone marrow failure Anemia, thrombocytopenia, ↓ number and function of normal WBCs. Leukemic cells infiltrate patient’s organs Splenomegaly Hepatomegaly Lymphadenopathy Bone pain, meningeal irritation, oral lesions(chloromas→ it is a solid collection of leukemic cells occurring outside of the bone marrow)

Investigation: Haematological investigations reveal a normochromic normocytic anaemia with thrombocytopenia in most cases. ↑ total WBC and blood film examination typically shows a variable numbers of blast cells. The bone marrow is hypercellular and typically contains many leukaemic blasts.

Prognosis of AML AML remains a devastating disease. Tumors with “good-risk” karyotypic abnormalities (t[8;21], inv[16]) are associated with a 50% chance of long-term disease-free The overall survival in all patients is only 15% to 30% with conventional chemotherapy AML associated with TP53 mutations has emerged as a subtype with a particularly poor prognosis. Targeted therapy with targeted treatment with all trans retionic acid (ATRA) promote the neoplastic promyelocytes to differentiate into neutrophils .