Leukaemia for bds

leukemia

1. Leukaemia Sunil Rao

2. Learning Objectives Define leukemia Identify the etiology of leukemia Discuss the definition, Pathophysiology , signs and symptoms, & management of: Acute L ymphoblastic leukaemia (ALL) Acute Myeloid Leukaemia (AML) Chronic Lymphocytic Leukaemia (CLL) Chronic Myeloid Leukaemia(CML)

3. Leukemia Definition It is 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.

4. 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)

5. 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

6. 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. marrow and blood

7. Acute vs. chronic leukemia 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

8. 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)

9. 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

10. 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

11. 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)

12. Differential Diagnosis Aplastic anemia Myelodysplastic syndromes Multiple myeloma Lymphomas Severe megaloblastic anemia Leukemoid reaction

13. Laboratory Tests CBC a. Anemia b. Trombocytopenia c. WBC High Normal Low Coagulation Studies (M3-DIC) Biochemical Studies (U/E, LFT) Cont..

14. Peripheral Blood smear – blasts in almost all cases Bone Marrow Examination (>20% blasts) Flow cyometry (Surface immunophenotype of blast cells) Cytogenetics (chromosomal analysis) CSF analysis (all ALL patients, some AML) HLA typing (for younger high risk patients)

15. Diagnostic methods of importance 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

16. Blood Film-Normal

17. Blood Film-Normal

18. Normal BM cells

19. AML

20. AML Auer rods

21. Discover the latest technology from Bayer                                    <> Bloodline Home About Educational Features Image Atlas Case Studies Private Lectures Conference Reviews Journal Articles Book Reviews Glossary Resources Conference Calendar Grants & Fellowships Hematology Links Full Text Journals Classifieds Specialties BMT/Stem Cell Cord Blood Thrombosis Hemostasis Laboratory Malignancies Pediatrics Red Cell Disorders Transfusion Medicine Veterinary News Hematology News BloodLink Newsletter Blood News Update Discussion Today's Discussion Create New Topic List by Topic Plasma Cells, Acute myelomonocytic (M-4) leukemia Clump of Plasma Cells most of which are small with a deep basophilic blue cytoplasm. Two cells in the center are partially smudged and show a paler cytoplasm and less dense and redder staining nuclear chromatin. Acute myelomonocytic (M-4) leukemia. Marrow - 100X                                                                                                                                                                                                                           Image ID: 0147-094               Copyright 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 responsibility for any use or misuse of this material and makes no warranty or representation of any kind with respect to the material available at this site.

22. Age 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 Acute Myeloid Leukaemia (AML) Prognostic factors in AML Wheatley K, Burnett AK, Goldstone AH et al . Br J Haem 1999; 107: 69-79 Grimwade D, Walker H, Oliver F et al . Blood 1998; 92: 2322-33

23. 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 Acute Myeloid Leukaemia (AML) Prognostic factors in AML Wheatley K, Burnett AK, Goldstone AH et al . Br J Haem 1999; 107: 69-79 Grimwade D, Walker H, Oliver F et al . Blood 1998; 92: 2322-33

24. 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 Acute Myeloid Leukaemia (AML) Treatment and prognosis of AML Wheatley K, Burnett AK, Goldstone AH et al . Br J Haem 1999;107: 69-79 Grimwade D, Walker H, Oliver F et al . Blood 1998; 92: 2322-33

25. Acute Lymphoblastic Leukaemia (ALL) Poor Prognostic Factors Age < 2 yrs and > 10 yrs Male sex High WBC count ( > 50 х 10 9 /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 Prognostic factors in ALL

26. ALL

27. Bone Marrow-ALL

28. Treatment of acute leukemias Specific therapy (chemotherapy) Supportive treatment Stages of Therapy Induction Consolidation Maintenance

29. (Treatment of acute leukemias ) Induction Obtained by using high doses of chemotherapy Severe bone marrow hypoplasia 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

30. (Treatment of acute leukemias ) Consolidation Different or same drugs to those used during induction Higher doses of chemotherapy Advantage: Delays relapse and improved survival

31. (Treatment of acute leukemias ) Maintenance Smaller doses for longer period Produce low neutrophil counts & platelet counts Objective is to eradicate progressively any remaining leukemic cells.

32. (Treatment of acute leukemias ) Supportive Care Vascular access (Central line) Prevention of vomiting Blood products (Anemia, ↓Plat) Prevention & treatment of infections (antibiotics) Management of metabolic complications

33. ALL vs AML ALL Induction Consolidation Maintenance CNS prophylaxis all patients AML Induction Consolidation No maintenance CNS – Selected group only

34. Definition: Neoplastic proliferations of mature haemopoeitic cells. Types: Chronic lymphocytic leukemia (CLL) Chronic myeloid leukemia (CML) CHRONIC LEUKEMIAS

35. Neoplastic proliferations of mature lymphocytes. Distinguished from ALL by Morphology of cells. Degree of maturation of cells. Immunologically immature blasts in ALL. CLL affects mainly elderly. CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL)

36. 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

37. 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

38. Stage (0-1) - lymphocytosis  LNS. (II) - above + hepatosplenomagely. (III-IV) - Anaemia. Hb< 10 g/l Thrombocytopenia. Platelet count : <100x10 9 /L. CLINICAL STAGING-CLL

39. LABORATORY TESTS-CLL CBC Lymphocyte count > 5 x 10 9 /L (5 -500 x 10 9 /L ). Platelets may be decreased Hb may be low Blood film PB immunophenotyping Bone marrow biopsy (needed before starting treatment) Imaging

40. 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 Progressive Symptoms Progressive Anemia or Thrombocytopenia Bulky LN, large spleen Recurrent Infections TREATMENT OF CLL

41. 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. CHRONIC MYELOID LEUKEMIA

42. CML is characterised by 3 distinct phases Chronic Phase: Proliferation of myeloid cells, which show a full range of maturation. Accelerated Phase decrease in myeloid differentiation occurs. Blast crisis (acute leukemia)

43. Symptoms Asymptomatic (50% of patients) Fatigue Weight loss Abdominal fullness and anorexia Abdominal pain, esp splenic area Increased sweating Easy bruising or bleeding CLINICAL PRESENTAITON OF CML

44. Splenomegaly (95%) ( 50% of patients have a palpable spleen ≥ 10 cm BCM, Usually firm and non-tender ) Hepatomegaly (50%) SIGNS OF CML

45. Chronic phase . Peripheral blood – neutrophil leukocytes 20,000 - >500, 000/  L basphilia  LAP score blasts < 5% Nucleated RBCs Thrombocytosis Anaemia DIAGNOSIS OF CML

46. 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)

47. 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

48. 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 ? 2 nd line TKIs

49. 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 TREATMENT OF CML

50. LA P Score Philadelphia Chromosome Basophilia Splenomegaly CML VS LEUKEMOID REACTION

51. Bone marrow or PBSC transplantation in leukemias Types of transplant Autologous transplant 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

52. Bone marrow or PBSC 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)

53. Complications of BMT