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Leukemia John H. Ward, MD Professor of Medicine Chief, Oncology Division Department of Internal Medicine University of Utah School of Medicine Huntsman.

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Presentation on theme: "Leukemia John H. Ward, MD Professor of Medicine Chief, Oncology Division Department of Internal Medicine University of Utah School of Medicine Huntsman."— Presentation transcript:

1 Leukemia John H. Ward, MD Professor of Medicine Chief, Oncology Division Department of Internal Medicine University of Utah School of Medicine Huntsman Cancer Institute Fall, 2005

2 Leukemia  Hallmark: proliferation of malignant cells in the bone marrow  Divided into: acute v. chronic acute v. chronic lymphoblastic v. myeloid (non-lymphoblastic) lymphoblastic v. myeloid (non-lymphoblastic)  Each type of leukemia has a different presentation, natural history, prognosis, and treatment.

3 Leukemia  Acute leukemias: rapid onset, rapid death if treatment is not successful  Chronic leukemias: natural history measured in years, even without initial treatment

4 Acute Leukemia  Presenting features: Anemia Anemia Fatigue, dyspnea, angina pectorisFatigue, dyspnea, angina pectoris Neutropenia - the leukocyte count may be high or low, but neutropenia is characteristic Neutropenia - the leukocyte count may be high or low, but neutropenia is characteristic Unexplained fever, serious infectionsUnexplained fever, serious infections Thrombocytopenia Thrombocytopenia Bruising, petechiaeBruising, petechiae Less common: lymphadenopathy, splenomegaly, skin infiltration, chloromas (tumors composed of malignant marrow cells) Less common: lymphadenopathy, splenomegaly, skin infiltration, chloromas (tumors composed of malignant marrow cells)

5 Acute Leukemia  Diagnosis: >20% blasts in the bone marrow  Categorized by H&E staining H&E staining Cytochemical stains (myeloperoxidase, NSE) Cytochemical stains (myeloperoxidase, NSE) Flow cytometry Flow cytometry Cytogenetics Cytogenetics

6 Acute Leukemia No evidence of maturation within blood or marrow

7 Acute Non-Lymphoblastic Leukemia (ANLL, AML)  Age: Adults - incidence increases with age Median age = 60 years Median age = 60 years Incidence = 10/100,000 per year in those Incidence = 10/100,000 per year in those > 60 years of age ~9700 cases per year in USA ~9700 cases per year in USA  Prognosis Untreated - ~ six weeks Untreated - ~ six weeks With treatment - median survival = 18 months With treatment - median survival = 18 months Some long term survivors Some long term survivors

8 Acute Non-Lymphoblastic Leukemia (ANLL, AML)  Treatment Anthracyclines + cytarabine Anthracyclines + cytarabine Upfront aggressive therapy with induction & consolidation Upfront aggressive therapy with induction & consolidation Stem cell transplantation for those in remission with appropriate physiology, age and match. Stem cell transplantation for those in remission with appropriate physiology, age and match.

9 ANLL - FAB Classification M0Undifferentiated leukemia MIAML without maturation M2AML with maturation M3 Acute promyelocytic leukemia M4Acute myleomonoblastic leukemia M5Acute monoblastic leukemia M6Erythroleukemia M7Megakaryoblastic leukemia

10 Myeloblasts Acute Myelogenous Leukemia

11 Acute Myelogenous Leukemia: Auer Rod

12 Blasts Acute Myelogenous Leukemia with differentiation

13 Promyelocyes Acute Promyelocytic Leukemia

14 Acute Monoblastic Leukemia

15 Acute Myelomoncytic Leukemia

16 ANLL - Clinical Correlates  M3: disseminated intravascular coagulation  M4, M5: skin & gum infiltration hypokalemia  M7: acute myelofibrosis

17 ANLL Initial evaluation and management  Define the phenotype of the leukemia  Correct metabolic abnormalities  Correct symptomatic anemia  Treat infection  Control bleeding  Begin tissue typing of potential transplant candidates

18 ANLL - Treatment  Induction therapy Anthracycline + cytarabine Anthracycline + cytarabine goal: to ablate abnormal clone and achieve a complete remission (CR) goal: to ablate abnormal clone and achieve a complete remission (CR) CR: normal blood counts with no increase in marrow blasts. CR: normal blood counts with no increase in marrow blasts. Chance of CR: 60-85% Chance of CR: 60-85%

19 Acute Promyelocytic Leukemia  Associated with a 15;17 translocation  Associated with severe DIC  May go into remission using all-trans retinoic acid  The only cause of DIC for which heparin is occasionally used

20 ANLL - Treatment  After a CR is obtained, consolidation therapy is needed. In its absence, CRs are short In its absence, CRs are short With consolidation, 20-40% may be long-term survivors With consolidation, 20-40% may be long-term survivors One form of consolidation therapy is marrow transplant One form of consolidation therapy is marrow transplant

21 ANLL Role of Marrow Transplant  Used as consolidation therapy of ANLL in 1st remission  Need HLA-matched donor, preferably a sibling  Typically requires a recipient aged 55 or less  May have cure rates of 50-60%, but upfront morbidity and mortality is problematic

22 ANLL Features conferring a poor prognosis  ANLL arising from myelodysplastic syndromes (AML with multilineage dysplasia)  ANLL after chemotherapy  Leukocyte count > 100 x 10 9 /L  Complex karyotype  Age > 60  Need for mechanical ventilation

23 Some Important Translocations in Leukemia  15;17 translocation seen in acute promyelocytic leukemia.  8;21 translocation seen in 10% of ANLL, associated with better response to therapy  Inv16, associated with bone marrow eosinophils and a good prognosis  11q23, associated with monocytic features – intermediate survival

24 Myelodysplastic Syndromes  Hypercellular marrow with peripheral cytopenias  Evidence of abnormal cellular maturation (ex. Dyserythropoiesis)  FAB classification subdivides disorders into clinically important groups  May evolve into acute leukemia

25 Myelodysplastic syndromes FAB classification  Refractory anemia (RA)  Refractory anemia with ringed sideroblasts (RARS)  Refractory anemia with excess blasts (RAEB)  Refractory anemia with excess blasts in transformation (RAEBIT)  Chronic myelomoncytic leukemia (CMML)

26 Myelodysplastic syndromes FAB WHO Classification  RA  RARS  RAEB  RAEBIT  CMML

27 Myelodysplastic syndromes FAB WHO Classification  RA  RARS  RAEB  RAEBIT now AML  CMML now in myelodysplastic/myeloproliferative disease

28 Myelodysplastic syndromes FAB WHO Classification  RA  RARS  RAEB RAEB-1: 5-9% blasts RAEB-1: 5-9% blasts RAEB-2: 10-19% blasts RAEB-2: 10-19% blasts

29 Myelodysplastic syndromes FAB WHO Classification  Refractory anemia (<5% blasts)  Refractory anemia with ringed sideroblasts (RARS) RCMD with ringed sideroblasts (RSCMD) RCMD with ringed sideroblasts (RSCMD)  Refractory anemia with excess blasts (RAEB) RAEB-1: 5-9% blasts RAEB-1: 5-9% blasts RAEB-2: 10-19% blasts RAEB-2: 10-19% blasts

30 Myelodysplastic syndromes FAB WHO Classification  Refractory anemia (<5% blasts)  Refractory anemia with ringed sideroblasts (RARS) RCMD with ringed sideroblasts (RSCMD) RCMD with ringed sideroblasts (RSCMD)  Refractory anemia with excess blasts (RAEB) RAEB-1: 5-9% blasts RAEB-1: 5-9% blasts RAEB-2: 10-19% blasts RAEB-2: 10-19% blasts

31 Myelodysplastic syndromes WHO classification  Refractory anemia <5% blasts Refractory anemia Refractory anemia Refractory cytopenias with multilineage dysplasia (RCMD) Refractory cytopenias with multilineage dysplasia (RCMD) MDS with isolated del (5q-) MDS with isolated del (5q-) MDS-unclassified (MDS-U) MDS-unclassified (MDS-U)  Refractory anemia with ringed sideroblasts (RARS) RCMD with ringed sideroblasts (RSCMD) RCMD with ringed sideroblasts (RSCMD)  Refractory anemia with excess blasts (RAEB) RAEB-1: 5-9% blasts RAEB-1: 5-9% blasts RAEB-2: 10-19% blasts RAEB-2: 10-19% blasts

32 MDS: IPSS score  Score predicts prognosis Features to be scored Features to be scored Marrow blastsMarrow blasts KaryotypeKaryotype Number of CytopeniaNumber of Cytopenia  Scores split this group of diseases into four prognostic groups

33 Myelodysplastic Syndromes  Survival depends on FAB subtype, or with new classification, IPSS score  Only curative treatment is BMT  Supportive care is best option for those in whom marrow transplant is not feasible  New option for 5q- syndrome: lenalidomide

34 ANLL Supportive Care  Erythrocyte transfusions - keep hematocrit >30%  Platelet transfusions - give when platelets <10 x 10 9 /L, or when at high bleeding risk  Antibiotics - empiric antibiotics with fever  Growth factors

35 Acute Lymphoblastic Leukemia (ALL)  Age: Children (75% < 6 years of age) less common in adults less common in adults  3200 cases/year  Prognosis Potential for cure is high in children Potential for cure is high in children long term remissions possible in adults long term remissions possible in adults  Treatment Induction therapy: vincristine + prednisone + other agents Induction therapy: vincristine + prednisone + other agents Consolidation and maintenance therapy Consolidation and maintenance therapy CNS prophylaxis mandantory CNS prophylaxis mandantory

36 Acute Lymphoblastic Leukemia

37 ALL  Most cases are Tdt positive  Most express CD10 (common ALL antigen)  Most are “pre-B cell” phenotype  15-20% T-cell lineage  5% B-cell phenotype

38 ALL  With induction therapy, CR is attained in 90% of patients.  Therapy usually lasts about 3 years  Without CNS prophylaxis, CNS relapse is common and devastating

39 Acute Lymphoblastic Leukemia  Bone marrow transplant reserved for second remission or very high-risk up front disease  High risk features Philadelphia chromosome + Philadelphia chromosome + B cell phenotype B cell phenotype Leukocyte count > 100 x 10 9 /L Leukocyte count > 100 x 10 9 /L Time to remission > 28 days Time to remission > 28 days

40 Chronic Leukemia  Often discovered because of an abnormal lab or an abnormal physical examination  Severe cytopenias characteristic of acute leukemia are seldom present at time of diagnosis

41 Chronic Myelogenous Leukemia  Age: adults  Prognosis: 3-4 years without BMT, cures possible with BMT  Treatment: Imatinib (Gleevec) Imatinib (Gleevec) Bone marrow transplant Bone marrow transplant Hydroxyurea +/- interferon; Hydroxyurea +/- interferon;

42 Chronic Myelogenous Leukemia  Leukocytosis with all degrees of myeloid differentiation in blood and marrow  Often associated with eosinophilia, basophilia, thrombocytosis  Splenomegaly is characteristic  LAP score is low (normal or high in other causes of leukocytosis)

43 Chronic Myelogenous Leukemia: Philadelphia Chromosome  9;22 translocation yields a chimeric gene termed bcr-abl bcr derived from chromosome 22 bcr derived from chromosome 22 abl derived from c-abl oncogene on chrom. 9 abl derived from c-abl oncogene on chrom. 9  Encodes a 210,000 MW protein - a tyrosine protein kinase  Ability to detect transcript by PCR may enable us to detect molecular remissions

44 Chronic Myelogenous Leukemia PMN Band Eosinophil Basophil Early Myeloid Cells

45 BCR-ABL translocation Chronic Myelogenous Leukemia

46  Disease terminates in “blast crisis” in 3-4 years; this responds to treatment poorly, and is rapidly fatal Blast crisis may have the phenotype of non- myeloid cells Blast crisis may have the phenotype of non- myeloid cells  Leukocyte count > 200 x 10 9 /L may be associated with leukostasis  Allogeneic BMT has been the treatment of choice if the patient is a candidate  Imatinib is a new option

47 Chronic Myelogenous Leukemia: Results of BMT  Five year survival > 60% with allogeneic BMT  < 25% of patients have an HLA-matched sibling  Matched unrelated donors (MUD) may be used

48 Chronic Myelogenous Leukemia Other approaches  Imatinib (Gleevec): Abl tyrosine kinase inhibitor: dramatic responses A classic example of targeted therapy A classic example of targeted therapy Probably not a cure, but a remarkable advance Probably not a cure, but a remarkable advance 87% major genetic response in chronic phase 87% major genetic response in chronic phase 55% response in blast crisis 55% response in blast crisis  Alpha-interferon 34.7 % major genetic response 34.7 % major genetic response  Hydroxyurea or alkylators can control leukocytosis

49 Chronic Lymphocytic Leukemia  Age: the elderly  Prognosis: may live for many years even without treatment  Treatment: Watchful waiting, purine nucleoside analogues (fludarabine), alkylators

50 Lymphocytosis Chronic Lymphocytic Leukemia

51  Clonal proliferation of lymphocytes -95 % with B-cell phenotype -95 % with B-cell phenotype  Usually detected as an asymptomatic lymphocytosis

52 Chronic Lymphocytic Leukemia  Hypogammaglobulinemia is common  Infection is the most common cause of death  Complications can include AIHA & ITP  May transform into an aggressive lymphoma Two staging systems exist: Rai & Binet Early stage disease has a survival equivalent to age- and sex-matched controls

53 Chronic Lymphocytic Leukemia  Most patients do not require specific treatment  Indications for treatment anemia anemia thrombocytopenia thrombocytopenia unsightly adenopathy unsightly adenopathy other complications other complications When treatment is needed, alkylators or purine nucleoside analogues are used

54 Hairy Cell Leukemia  Age: adults  Prognosis: many years  Treatment: Adenosine deaminase inhibitors (cladribine)

55 Hairy cells: Cancerous leukocytes in the blood of a patient with hairy-cell leukaemia Lancet Oncology Cover, February, 2003

56 Hairy Cell Leukemia

57  Pancytopenia, splenomegaly  Marrow full of TRAP + lymphoid cells  Cells have projections when viewed with phase contrast or electron microscopy  Very responsive to purine nucleoside analogues such as cladribine

58 Questions? Feel free to contact me  Office: 2141, Huntsman Cancer Institute  Office phone:  Pager: 

59

60 Lymphoma Classification I. Good Ones. (include nonconvoluted diffuse centrilobulated histioblastoma, immune binucleolar hyperbolic folliculated macrolymphosaracoma, T 2 - terminal transferase-negative bimodal prolymphoblastic leukosarcoma, Jergen-Kreuzart- Munier-Abdullah syndrome and reticulated histioblastic pseudo-Sezare IgM-secreting folliculoma). Characteristic: small tumor that does not recur after treatment

61 Lymphoma Classification II. Not-so-good Ones. (formerly “hairy-cell” pseudoincestuoblastoma, quasiconvoluted binucleate germinoma, sarcoblastiocytoma, Syrian variant of heavy chain disease, and German grossobeseioma). Characteristic: such tumors disappear with treatment but return and cause appreciable mortality

62 Lymphoma Classification III. Really bad ones. (include farscial mononuclear diffuse convoluted pseudoquasihistiolymphosarcomyleoblastoma, IgG variant of fragmented plasmatic gammopathy, triconvoluted ipsilateral rhomboid fever, Armour’s hyperthermic caninoma, and Hohner’s harmonica). Characteristic: regardless of treatment, these tumors keep growing

63 Lymphoma Classification IV. Ones that are not what they seem. (include gall bladder disease, appendicitis, shotgun wounds, and ingrown toenails). Characteristic: these conditions are not actually lymphomas but are included for the sake of completeness


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