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Leukaemia for bds
Leukaemia is a group of malignant blood disorders affecting the bone marrow and blood-forming tissues. There are four main types classified by whether the affected cells are lymphoid or myeloid, and whether the disease course is acute or chronic. Acute leukemias involve immature blast cells and a rapid progression, while chronic leukemias involve more mature cells and a slower course. The document defines each type and discusses their signs, symptoms, diagnosis, prognostic factors and treatment approaches.
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Leukaemia for bds
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- 2. Learning Objectives •Define leukemia • Identify the etiology of leukemia • Discuss the definition, Pathophysiology , signs and symptoms, & management of: Acute Lymphoblastic leukaemia (ALL) Acute Myeloid Leukaemia (AML) Chronic Lymphocytic Leukaemia (CLL) Chronic Myeloid Leukaemia(CML)
- 5. Leukemia Definition Itis a group of malignant disorders, affecting the blood and blood –forming tissue of the bone marrow lymph system and spleen. A etiology Combination of predisposing factors including genetic and environmental influences. Chronic exposure to chemical such as benzene Radiation exposure. Cytotoxic therapy of breast, lung and testicular cancer.
- 6. Classification of leukemias Two major types (4 subtypes) of leukemias Acute leukemias Acute lymphoblastic leukemia (ALL) Acute myelogenous leukemia (AML) (also "myeloid" or "nonlymphocytic") Chronic leukemias Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML) (Within these main categories, there are typically several subcategories)
- 7. Myeloid vs Lymphoid • Any disease that arises from the myeloid elements is a myeloid disease ….. AML, CML • Any disease that arises from the lymphoid elements is a lymphoid disease ….. ALL, CLL
- 8. Acute vs. chronicleukemia • 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. marrow and blood
- 9. Acute vs. chronicleukemia • Leukemias are classified according to cell of origin: • Lymphoid cells ALL - lymphoblasts CLL – mature appearing lymphocytes • Myeloid cells AML – myeloblasts CML – mature appearing neutrophils • On a CBC, if you see: • Predominance of blasts in blood consider an acute leukemia • Leukocytosis with mature lymphocytosis consider CLL • Leukocytosis with mature neutrophilia consider CML
- 10. Acute leukemias Definition:Malignancies of immature hematopeotic cells. (> 20% blast cells in the bone marrow) Types: Acute Myeloid Leukaemia (AML) Acute Lymphoblastic leukemia (ALL) Groups: Childhood (< 15) > 80% ALL Adult (> 15) > 80% AML Elderly (> 60 years)
- 12. Acute leukemias Etiology • Drugs & chemicals • Alkylating agents (Chlorambucil, N mustard, Melphalan) Topoisomerase inhibitors (Etoposide) • Benzene • Ionizing radiation • Viruses HTLV-1 (Adult T-cell leukemia Lymphoma) • Genetic disorders Down’s syndrome • Myelodysplastic syndrome
- 13. Clinical presentation Symptoms • Usual 1-3 Month History : MDS – 1yr • (Features of BM failure) • Fatigue, malaise, dyspnea (anemia) • Bleeding eg after dental procedure Easy bruisability Severe epistaxis • Fever (infections) • Bone Pain
- 14. Clinical Presentation Signs Pallor Hemorrhage from the gums, epistaxis, skin, fundus, GI tract, urinary tract Hepato-splenomegaly Enlarged lymph nodes Gum (hypertrophy) or skin infiltration (M5) Fever (sepsis, pneumonia, peri-rectal abscess)
- 15. Differential Diagnosis 1.Aplastic anemia 2. Myelodysplastic syndromes 3. Multiple myeloma 4. Lymphomas 5. Severe megaloblastic anemia 6. Leukemoid reaction
- 16. Laboratory Tests 1.CBC a. Anemia b. Trombocytopenia c. WBC High Normal Low 2. Coagulation Studies (M3-DIC) 3. Biochemical Studies (U/E, LFT) Cont..
- 17. 4. Peripheral Bloodsmear – blasts in almost all cases 5. Bone Marrow Examination (>20% blasts) 6. Flow cyometry (Surface immunophenotype of blast cells) 4. Cytogenetics (chromosomal analysis) 5. CSF analysis (all ALL patients, some AML) 6. HLA typing (for younger high risk patients)
- 18. Diagnostic methods ofimportance • Bone marrow aspirate & Romanowsky stain (morphology) Enumeration of blasts, maturing cells, recognition of dysplasia • Cytochemistry Myeloperoxidase, Sudan Black B, esterases to determine involved lineages • Immunophenotyping Defines blast cell lineage commitment as myeloid, lymphoid or biphenotypic • Cytogenetics & molecular studies (FISH, PCR) Detects clonal chromosomal abnormalities, including those of prognostic importance
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- 24. Image ID: 0147-094 Copyrigh t 2001 - Carden Jennings Publishing Co., Ltd. All rights reserved. The material available at this site is for educational purposes only and is NOT intended for any diagnostic, clinically related, or other purpose. Carden Jennings Publishing Co., Ltd., assumes no responsibili ty for any use or misuse of this material and makes no warranty or representat ion of any kind with respect to the material available at this site.
- 27. Acute Myeloid Leukaemia(AML) • Age Prognostic factors in AML Above the age of 50 years the complete remission rate falls progressively • Cytogenetics Three risk groups defined – Good risk: patients with t(8;21), t(15;17) and inv/t(16) – Intermediate risk: Normal, +8, +21, +22, 7q-, 9q-, abnormal 11q23, all other – Poor risk: patients with -7, -5, 5q-, abnormal 3q and complex karyotypes 1. Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999; 107: 69-79 2. Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33
- 28. Acute Myeloid Leukaemia(AML) Prognostic factors in AML • Treatment response – Patients with >20% blasts in the marrow after first course of treatment have short remissions (if achieved) and poor overall survival • Secondary AML – Patients with AML following chemotherapy or myelodysplasia respond poorly • Trilineage myelodysplasia – Patients with trilineage myelodysplasia have a lower remission rate 1. Wheatley K, Burnett AK, Goldstone AH et al. Br J Haem 1999; 107: 69-79 2. Grimwade D, Walker H, Oliver F et al. Blood 1998; 92: 2322-33
- 29. Acute Myeloid Leukaemia(AML) Treatment and prognosis of AML • Intensive chemotherapy – Patients < 55 years old: 80% remissions – Patients > 55 years old: progressive reduction in remission rate • Bone marrow (stem cell) transplantation – Autologous and allogeneic transplants reduce the relapse rate • Importance of cytogenetics for prognosis in children and adults < 55 years old • Good risk cytogenetic group – 91% remissions, 65% five year survival 1. Wheatley K, Burnett AK, Goldstone AH et al . Br J Haem 1999;107: 69-79 2. Grimwade D, Walker H, Oliver F et al . Blood 1998; 92: 2322-33
- 30. Acute Lymphoblastic Leukaemia(ALL) Prognostic factors in ALL Poor Prognostic Factors • Age < 2 yrs and > 10 yrs • Male sex • High WBC count ( > 50 х109/L) • Presence of CNS disease • Cytogenetics Good risk Poor risk Hyperdiploid (>50 ch) Hypodiploid, t(9:22), t(4:11) • Bone Marrow: Blasts present on day 14 • Day 28:No complete response
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- 33. Treatment of acuteleukemias 1. Specific therapy (chemotherapy) 2. Supportive treatment Stages of Therapy a. Induction b. Consolidation c. Maintenance
- 34. (Treatment of acuteleukemias) Induction Obtained by using high doses of chemotherapy 1. Severe bone marrow hypoplasia 2. Allowing regrowth of normal residual stem cells to regrow faster than leukemic cells. Remission Normal neutrophil count Normal platelet count Normal hemoglobin level Remission defined as < 5% blast in the bone marrow
- 35. (Treatment of acuteleukemias) Consolidation • Different or same drugs to those used during induction • Higher doses of chemotherapy • Advantage: Delays relapse and improved survival
- 36. (Treatment of acuteleukemias) Maintenance • Smaller doses for longer period • Produce low neutrophil counts & platelet counts • Objective is to eradicate progressively any remaining leukemic cells.
- 37. (Treatment of acuteleukemias) Supportive Care 1. Vascular access (Central line) 2. Prevention of vomiting 3. Blood products (Anemia, ↓Plat) 4. Prevention & treatment of infections (antibiotics) 5 Management of metabolic complications
- 38. ALL vs AML ALL Induction Consolidation Maintenance CNS prophylaxis all patients AML Induction Consolidation No maintenance CNS – Selected group only
- 39. CHRONIC LEUKEMIAS Definition:Neoplastic proliferations of mature haemopoeitic cells. Types: Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML)
- 40. CHRONIC LYMPHOCYTIC LEUKAEMIA(CLL) Neoplastic proliferations of mature lymphocytes. Distinguished from ALL by a. Morphology of cells. b. Degree of maturation of cells. c. Immunologically immature blasts in ALL. d. CLL affects mainly elderly.
- 41. SYMPTOMS of CLL May be entirely absent in 40% Weakness, easy fatigue, vague sense of being ill Night sweats Feeling of lumps Infections esp pneumonia
- 42. PHYSICAL EXAMINAITON-CLL Pallor Lymphoadenopathy a. Cervical, supraclavicular nodes more commonly involved than axillary or inguino-femoral b. Non-tender, not painful, discrete, firm, easily movable on palpation Splenomegaly, mild to moderate Hepatomegaly
- 43. Stage CLINICAL STAGING-CLL (0-1) - lymphocytosis LNS. (II) - above + hepatosplenomagely. (III-IV) - Anaemia. Hb< 10 g/l Thrombocytopenia. Platelet count : <100x109/L.
- 44. LABORATORY TESTS-CLL CBC Lymphocyte count > 5 x 109/L (5 -500 x 109/L ). Platelets may be decreased Hb may be low Blood film PB immunophenotyping Bone marrow biopsy (needed before starting treatment) Imaging
- 45. TREATMENT OF CLL Observation Chemotherapy. Oral chlorambucil Fludarabine, cyclo Immunotherapy Anti-CD 20 (rituximab), Anti-CD 52 (Alemtuzumab) FC-R is the current standard Indications for starting chemotherapy a. Progressive Symptoms b. Progressive Anemia or Thrombocytopenia c. Bulky LN, large spleen d. Recurrent Infections
- 46. CHRONIC MYELOID LEUKEMIA CML is a clonal stem cell disorder characterised by increased proliferation of myeloid elements at all stages of differentiation. Incidence increases with age, M > F.
- 47. CML is characterisedby 3 distinct phases a) Chronic Phase: Proliferation of myeloid cells, which show a full range of maturation. b) Accelerated Phase decrease in myeloid differentiation occurs. c) Blast crisis (acute leukemia)
- 48. CLINICAL PRESENTAITON OFCML Symptoms Asymptomatic (50% of patients) Fatigue Weight loss Abdominal fullness and anorexia Abdominal pain, esp splenic area Increased sweating Easy bruising or bleeding
- 49. SIGNS OF CML Splenomegaly (95%) (50% of patients have a palpable spleen ≥ 10 cm BCM, Usually firm and non-tender) Hepatomegaly (50%)
- 50. DIAGNOSIS OF CML Chronic phase. Peripheral blood – neutrophil leukocytes 20,000 - >500, 000/ L basphilia LAP score blasts < 5% Nucleated RBCs Thrombocytosis Anaemia
- 51. CYTOGENETICS OF CML Philadelphia (Ph) chromosome is an acquired cytogenetic abnormality in all leukaemia cells in CML Reciprocal translocation of chromosomal material between chromosome 22 and chromosome 9. t(9;22)
- 58. CML-Treatment Response Criteria • Hematological response Normalisation of blood count • Cytogenetic response Major cytogenetic response 1-35% Ph +ve cells in metaphase Minor cytogenetic response 36-65% Ph +ve cells in metaphase • Molecular response Absence of BCR/ABL gene
- 59. CML-Principles of Treatment • Control & prolong chronic phase (non-curative) - Tyrosine kinase inhibitors-Imatinib (Glivec) - Alpha-Interferon - Oral chemotherapy (Hydroxyurea, ARA-C) • Eradicate malignant Clone (curative) - Allogeneic BM/stem cell transplantation - Alpha Interferon? - Imatinib? 2nd line TKIs
- 60. TREATMENT OF CML • Tyrosine kinase inhibitor (TKI) Imatinib (Glivec) is the first line treatment • In resistent cases 2nd line TKIs (Nilotinib, Dasatinib, Bosutinib) very useful • Allogenic bone marrow trasnsplantation can be curative in pts resisrant to TKIs but has significant complications & mortality Accelerated and blast phase Glivec, 2nd line TKIs Treat like AML or ALL followed by BMT
- 61. CML VS LEUKEMOID REACTION 1. LA P Score 2. Philadelphia Chromosome 3. Basophilia 4. Splenomegaly
- 62. Bone marrow orPBSC transplantation in leukemias Types of transplant 1. Autologous transplant 2. Allogeneic Transplant Purpose of transplant Autologous -To deliver a high dose of chemo to kill any residual cancer (lymphoma, multiple myeloma) Allogeneic -To eradicate residual leukemia cells -Graft vs leukemia effect
- 63. Bone marrow orPBSC transplantation in leukemias Technique of transplantation MHC + HLA matching Chemotherapy Total body irradiation GVHD prophylaxis Complications of transplantation • Prolonged BM suppression (graft failure) • Serious infections • Mucositis • Graft versus host disease (GVHD)
- 64. Complications of BMT Lung toxicity 13% Other Organ toxicity 4% Hemorrhage 5% Other 5% Relapse 12% Infection 26% GVHD 29% VOD 6%