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2leukemia
Leukemia is a group of cancers that affect the blood and bone marrow. This document discusses the main types of leukemia: 1. Acute myelogenous leukemia (AML) is characterized by increased proliferation of immature myeloid cells in the bone marrow. It accounts for about one-third of adult leukemias. 2. Acute lymphoblastic leukemia (ALL) is most common in children and is characterized by increased lymphoblasts in the bone marrow. About 85% of ALL cases are B-cell ALL. 3. Chronic myelogenous leukemia (CML) is a myeloproliferative neoplasm characterized by increased and unregulated growth of predominantly granulocytic
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2leukemia
- 1. leukemia By Dr. DamenaM.(MD)
- 2. Presentation out line •introduction • Acute myelogenous leukemia • Acute lymphoblastic leukemia • Chronic myelogenous leukemia • Chronic lymphoblastic leukemia
- 3. Introduction Definition • Leukemia area group of malignant disorder of hematopoietic tissue characterized by increased no. of blast cells in bone marrow. • This cells are proliferate in uncontrolled fashion and replace normal bone marrow elements.
- 4. • Classification • Acute:havebrief symptomatic period with short life expectancy without treatment • Myelogenous • lymphoblastic • Chronic:- the patient are un well for years and survival is long ( usually in years) • Myelogenous • Lymphoblast • Sub leukemic leukemia:- normal or sub-normal leucocyte count but blasts ( immature blood cells)are seen on peripheral morphology • Aleukemic leukemia:- normal or sub normal leucocyte count and also no blast seen on peripheral morphology. diagnosis is by taking bone marrow biopsy and seeing blast cells.
- 5. RBC Bone Marrow Hematopoiesis Pluripotent StemCell Myeloid Stem Cell Lymphoid Stem Cell Platelet PMN Eos Baso Mono T- lympho blast B- lympho blast B-cell Erythro- blast Myeloblast Meg- blast T-cell Plasma cell Monoblast
- 6. Acute myelogenous leukemia •AML is characterized by a clonal proliferation of myeloid precursors with a reduced capacity to differentiate into more mature cellular elements. • As a result, there is an accumulation of leukemic blasts or immature forms in the bone marrow, peripheral blood, and occasionally in other tissues, with a variable reduction in the production of normal red blood cells, platelets, and mature granulocytes.
- 8. INCIDENCE • In 2013,the estimated number of new AML cases in the United States was 14,590. • The incidence of AML is ~3.5 per 100,000 people per year • the age-adjusted incidence is higher in men than in women (4.5 vs 3.1) • AML incidence increases with age; it is 1.7 in individuals age <65 years and 15.9 in those age >65 years. • The median age at diagnosis is 67 years.
- 9. ETHIOLOGY • Exact etiologyof AML is unknown. • Heredity • Genetic fragility • Bloom syndrome= autosomal disorder • Fanconi anemia =reduce produced cells • Wiskott Aldrich =thrombocytopnia • Down, Klinefelter, Patau syndromes • Myeloproliferative syndromes • Radiation exposure; High dose like in atomic bomb survival of japan. Therapeutic radiation have no or little effect • Chemical and other exposures • Benzene, cigarette smoking, petroleum products • herbicides?, pesticides? • Drugs • Topoisomerase II inhibitors (e.g etopisode), alkylating agents • Chloramphenicol, chloroquine
- 10. Classification • WHO classification-based on • Morphology • Clinical features, and • Cytogenetic and molecular abnormalities • Uses 20% blast cut-off for a diagnosis of AML • Useful for targeted therapy • FAB (French-American-British )classification • Based on morphology and cytochemistry • AML is defined as the presence of >30% blasts in the BM • 5-30% blast is considered as MDS=myelodysplastic syndrome • Still utilized by pathologists due to its simplicity
- 11. FAB Classification ofAML • M0- undifferentiated acute myeloblastic leukemia • M1 -AML with minimal maturation • M2- AML with maturation • M3 -Acute promyelocytic leukemia • M4- Acute myelomonocytic leukemia • M4Eo - Acute myelomonocytic leukemia with eosinophilia • M5- Acute monocytic leukemia • M6 -Acute erythroid leukemia • M7 -Acute megakaryoblastic leukemia
- 12. Clinical feature • Symptomsare the consequence of anemia, leukocytosis, leukopenia, or thrombocytopenia • Fatigue- the most common symptom • Anorexia and weight loss • Fever with or without an identifiable infection • Bleeding and easy bruising • Occasionally, bone pain, LAP, nonspecific cough, headache, or diaphoresis
- 13. • Myeloid sarcoma-a tumor mass consisting of myeloid blasts occurring at anatomic sites other than bone marrow • Common sites include the skin, lymph node, GIT, soft tissue, and testis • Physical findings • Fever, hepatomegaly, splenomegaly, and LAP • Sternal tenderness • Bleeding from GIT, pulmonary, or intracranial • Retinal hemorrhages • Infiltrations of the gingivae, skin, soft tissues, or meninges with leukemic blasts
- 16. Lab evluation • CBC •25-40% of pts have WBC count <5000/µl, and 20% have counts >100,000/µl • Anemia is usually present and can be severe • Platelet count <100,000/µl- 75% of pts • Serum uric acid and LDH • LFT and RFT • Serum electrolytes • Bone marrow aspirate and biopsy- for morphology, cytogenetics, flow cytometry, molecular studies • Lumbar puncture for those with symptoms of CNS involement
- 17. • Viral serologiesfor HIV, CMV, HSV-1, varicella-zoster • HLA typing for potential allogenic HSCT • PA and lateral chest X-ray • echocardiography • Diagnostic criteria • Previously >30% blasts on BM aspirate (per FAB criteria) • Recently changed to > 20% blasts on BM aspirate (per WHO criteria)
- 19. Treatment of AML Goalfor complete remission • platelet count greater than 100,000 • neutrophil count greater than 1000 • BM with 5% or less blasts with no Auer rods • No circulating blasts • No extramedullary leukemia • Molecular complete remission : no evidence of leukemic cells in BM even with sensitive tests (eg, PCR, flow cytometry) • If in complete remission for >3 yrs without relapse → potentially cured (<10% chance of relapse)
- 20. Remission induction therapy •Commonly anthracycline (ie, daunorubicin, idarubicin) and cytarabine → (“3+7 regimen”) • Cytarabine has ample CNS penetration so no need for prophylactic intrathecal chemotx (also, ↓ risk in patients with AML compared to ALL) • 60-80% achieve complete remission Post remission therapy 1. Consolidation – longer survival than maintence alone – typically high dose cytarabine 2. Maintenance – continue chemotx monthly for 4-12 months – nonmyelosuppressive doses
- 21. Increasingly, hematopoietic celltransplantation is used in patients with AML after 1st remission in those with poor/intermediate prognostic factors. • Also allogenic/autologous transplant in those with relapse or 2nd remission • autologous with higher relapse rates • Used in those without HLA matched donor • Standard therapy → remission rates of 60-80% with median remission durations of 1 yr • less than 20% achieve long-term remission free survival • Therapy is altered in older individuals (esp. those with poor performance status) • AML believed to be a clinically/biologically distinct entity in older individuals → remission rates of 45% in those > 60 yo with less than 10% long-term remission free survival • low dose cytarabine +/- hydroxyurea investigational therapy palliative care
- 22. • Supportive care •G-CSF • platelet transfusions • PRBCs (leukodepleted, irradiated) • Prophylactic antibiotics • Cefepime/ceftazidime • fluconazole (candidiasis) • acyclovir (HSV, VZV) • Prevention of hyperuricemia with hydration and allopurinol and/or rasburicase
- 24. Prognostic Factors inAML • Favorable • younger age (<50) • WBC <30,000 • Favorable cytogenetics and molecular findings • Achievement of CR with single course of chemotherapy • Unfavorable • older age (>60) • Poor performance status • WBC >100,000 • Elevated LDH • prior MDS or myeloproliferative disorders • AML developing after treatment with cytotoxic agents • Comorbidities • A prolonged symptomatic interval with cytopenias preceding diagnosis
- 25. ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) •Commonest form of malignancy in childhood • Peak incidence at 4 – 5 yrs of age • Acute onset with short history of duration • 85% are B cell , 15% are T cell
- 26. PREDISPOSING FACTORS • HEREDITARY •AQUIRED • Ionizing radiations • Therapeutic radiations • Nuclear fallout • Diagnostic X-rays • Chemical agents
- 27. Clinical presentation• FEVER •FATIGUE • BONE /JOINTS PAIN • WEIGHT LOSS • PURPURA AND BLEEDING MANIFESTATION • LYMPHADENOPATHY- • HEPATOSPLENOMEGALY • STERNAL TENDERNESS • MEDIASTENAL MASS
- 28. FAB CLASSIFICATION ALLL1 ALL L2 ALL L3 In childhood – L1 is the most common type In adults – L2 is the most common type
- 29. FAB classification Morphology L1L2 L3 1 Size of blast Small Large heterogeneous Large homogenous 2 Cytoplasm Scanty Moderate Moderate, intensely basophilic 3 N/C Ratio High Lower Lower 4 Cytoplasmic vacuoles +/- +/- Prominent 5 Nuclear membrane Regular Irregular with clef ting Regular 6 Nucleoli Invisible / indistinct Prominent 1-2 Prominent 1-2
- 30. DIAGNOSIS OF ACUTELEUKEMIA • Peripheral Blood smear • Bone marrow aspiration smear • Cytochemistry • Immunophenotyping • Cytogenetic analysis • Molecular genetic analysis
- 31. PERIPHERAL BLOOD EXAMINATION Total leukocyte count raised , normal or low Normocytic normochromic anaemia Thrombocytopenia
- 32. BONE MARROW EXAMINATION •Hypercellular • Normal hematopoietic elements diminished • Increased blasts
- 33. PROGNOSTIC FACTORS Factor Goodprognosis Bad prognosis Race White Black Age 2-8 yrs <1yr.,adult, >10 yrs Sex Female Male Meningeal involvement - + Lymphadenopathy, liver, spleen - Massively enlarged Mediastinal mass - + TLC <20x109 /L >50 x109 /L Type of ALL L1 L2,L3 Cytogenetics Hyperdiploidy >50 chromosomes Pseudodiploidy, t (4;11),t (9;22), BCR-ABL fusion m RNA, MLL-AF4 fusion mRNA. Immuno-phenotype B-ALL,CD 10+, Early pre-B cell T-ALL in children
- 34. Treatment • Induction phase •High dose chemotherapy • Consolidation phase • High dose systemic therapy • CNS prophylaxis • Maintenance phase • Prevent relapse • Effect cure • Supportive care • The overall cure rate in children is 90%, while 50% of adults are long-term disease-free survivors
- 35. ALL Vs AML ALLAML Age Mainly children Mainly adults Lymphadenopathy Usually present Usually absent Hepatosplenomegaly +ve mild +ve mild Gum hypertrophy -ve +ve in M4/M5 Skin infiltration -ve +ve in M4/M5 CNS involvement +ve in some +ve in some Granulocytic sarcoma -ve +ve in few cases Mediastinal mass +ve in T-ALL - Associated DIC -ve +ve in M3 Serum muramidase Normal In M4/M5 (monocytic type) Prognosis Good Bad
- 36. Chronic Myeloid Leukemia (CML) •is a clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22 called Philadelphia chromosome • Occurs more often in men • Incidence increases with age • High doses of ionising radiation can increase the occurrence of CML • No clear correlation with exposure to cytotoxic drugs has been found, and no evidence suggests a viral etiology
- 37. Pathophysiology • Genetic hallmarkof CML is the presence of BCR-ABLfusion gene product • The fusion protein is a result of reciprocal translocation between the abelson oncogene on chromosome 9 and break point cluster region on chromosome 22. • Attachment of the BCR sequences to ABL1 results in three critical functional changes I. The ABL protein becomes constitutively active as a tyrosine kinase enzyme, activating down stream kinases that prevent apoptosis II. The DNA-protein-binding activity of Abl is attenuated; and III. The binding of Abl to cytoskeletal actin microfilaments is enhanced
- 39. Clinical presentation Symptoms • Fatigue,malaise •Weight loss • Early satiety • Left upper quadrant pain or mass • Easy bruising ,bleeding • Fever Uncommon presentation • Acute gouty arthritis,priapism,myocardial infarction,venous thrombosis,visual disturbance
- 40. Signs • pallor • Splenomegaly •Sternal tenderness • Lymhadenopathy • Hepatomegaly • Purpura • Retinal haemorrhage
- 41. Diagnostic approach Peripheral blood •Granulocytic leukocytosis>50*10p9/l • Predominance of neutrophils and increased % of myelocytes • Absolute basophilia • Platelets are normal or increased in number Bone marrow • Marrow is hypercellular with granulocytic predominance • Megakaryocytes are increased in number with abnormal morphology • Increase in reticulin fibrosis • Blasts less than 5%
- 42. Phases of CML chronicphase • Elevated WBCs • <5% circulating blasts • Majority of the cells are myelocytes, metamyelocytes, and band forms Accelerated phase • Blasts 10-20% in peripheral blood and/or bone marrow • Basophils >20% in peripheral blood • Increasing degrees of anemia unaccounted for by bleeding or therapy • Persistent thrombocytopenia • Cytogenetic evidence of clonal evolution
- 43. Blast crisis phase •Blast > 20%- acute leukemia • Extramedullary blast proliferation • Large aggregates or clusters of blast in bone marrow • Hyposegmented neutrophils may appear • Occurrence of de novo blast crisis or following imatinib therapy is rare
- 44. Treatment • Drugs • Stemcell transplant • Leukaphresis and splenectomy drugs • Imatinib mesylate,dasatinib,nilotinib • Hydroxyurea • busulphan • Interferon-alpha • Homoharringtonine • Anagrelide • Cytarabin
- 45. Imatinib • It isan ABL specific tyrosine kinase inhibitor • Imatinib induces apoptosis in cells expressing BCR/ABL • Dose is 400mg/day • It should achieve cytogenetic remission by 6months and molecular remission by 18 months • Side effects-edema,pleural and pericardial effusion,nausea,vomiting,diarrhoea,muscle cramps,skin rash,bone pain and arthralgia.myelosuppression.
- 46. Hydroxy urea • Inhibitorof ribonucleotide reductase • Lower the blood counts in 1-2 days • Dose is 500-3000 mg/day • Side effect-nausea and skin rash • Given for patients intolerant to imatinib Busulphan • Gradually lowers the blood counts • Dose-6-10 mg/day • Should not be used in patients expected to undergo bone marrow transplantation
- 47. Allogenic HSCT • Outcomedepends on patients age, phase of disease, type of donor, preparative regimen, graft Vs host disease, post transplantation treatment • Patients age should be less than 70 years. transplantation from donor should be HLA matched • Peripheral blood can be used a source of haemotopoietic progenitor cells. preoperative regimen like cyclophosphamide plus total body irradiation is used • Complications-graft Vs host disease
- 48. Chronic lymphocytic leukemia (CLL) •Chronic Lymphocytic Leukemia (CLL) is a low-grade Non-Hodgkin lymphoma • It is main characteristic is • proliferation of malignant clone of mature- appearing cells in the bone marrow with leukemic component • absolute lymphocytosis in the peripheral blood. • In 90% of cases it originates from B-cell
- 49. Epidemiology • B-cell chroniclymphocytic leukemia(CLL) -the most common lymphoproliferative disorder in Western countries • incidence • 5/100,000-for males and • 2.5/100,000 for females • More common in whites than blacks • Disease of older adults – median age-65-68 years • CLL is exceedingly rare in children
- 50. Clinical features • hasa chronic course • could be asymptomatic • often is diagnosed accidentally on a routine blood count • In symptomatic patients • Splenomegaly • LAP-the lymph nodes are nontender, non matted or fixed to surrounding tissue • Rarely- malaise, easy fatigability, weight loss, night sweats • these symptoms usually correlate with the overall tumor load
- 51. CLINICAL FEATURES • Anemia,thrombocytopenia, neutropenia due to- • disease progression within the bone marrow; • autoimmune complication; • Hypersplenism; or • treatment side effects • Symptoms of immune defficiency- • hypogammaglobulinemia – pulmonary bacterial infections; • T-cell deficiency-more often result of treatment- high risk of viral and opportinistic infections • Autoimmune manifestations such as • autoimmune thrombocytopenia, • Coombs positive hemolytic anemia, or • pure red cell aplasia
- 52. LABORATORY STUDIES • Increasein the number of mature-appearing lymphocytes in circulation to more than 5000/microL • In the advance stages – anemia, thrombocytopenia • In patients with very large tumor burden-elevated serum lactic dehydrogenase (LDH), beta2 – microglobulin and uric acid levels • In 5%- serum protein electrophoresis detects M-components(paraprotein) • Often- hyppogammaglobulinemia • Often- Coombs test is positive
- 53. LABORATORY STUDIES • Peripheralsmear shows increased numbers of small, mature appearing lymphocytes • Smudge cells • Bone marrow generally shows a diffuse infiltration of small, mature-appearing lymphocytes
- 54. DIAGNOSIS - Absolute lymphocytosis-> 5000/ microL mature-appearing lymphocytes in circulation - Diffuse infiltration of bone marrow of small , mature –appearing lymphocytes - Typical immunophenotyping of B-cells-CD19+; CD5+; CD23+; CD20+; low amounts of sIg
- 56. TREATMENT AND PROGNOSIS Prognosticfactors: • advanced stage • lymphocyte doubling time < 6 months • cytogenetic abnormalities , esp. del 17 • expression of CD38 and ZAP-70 • elevated LDH and beta 2 -microglobulin
- 57. Treatment and Prognosis •The treatment of CLL with chemotherapy with or without transplantation is never curative • When patients are asymptotic, without large tumor burden and unfavorable prognostic factors it is better option to delay treatment till progression of the disease happens . • Chlorambucil • oral alkylating agent • response is obtained in 60-70% but is usually partial and last less 20 months
- 58. Treatment and Prognosis •Fludarabine • purine analog • The overall response rate is 75% with a mean duration 25 months • could be administated alone( complete response-20%) or in combination with Cyclophosphamide ( complete response- 40%) • Alemtuzumab- • recombinant CD 52 –antibody which is shared by CLL-B cells and normal T cells • Side effects- “ first dose effect”- rigors, fever, hypotension and respiratory distress; severe immunosupression, reactivation of CMV
- 59. Complications 1. Autoimmune disease: •Hemolytic anemia and thrombocytopenia. The treatment include corticosteroids. • Pure red cell aplasia- usually responds to cyclosporin 2. Severe infections: • antibiotics, • antiviral agents, • sometimes administration of i.v. gamma globulin 3. Richter syndrome: • transformation to diffuse large cell lymphoma or prolymphocytic leukemia • it is suspected when the disease’s course changes abruptly
- 60. Thank you verymuch QUESTIONS???