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Leukemia

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Huntsman Cancer Institute ... onset, rapid death if treatment is not successful ... a cure, but a remarkable advance. 87% major genetic response in ... – PowerPoint PPT presentation

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Title: Leukemia


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
  • 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
  • Fatigue, dyspnea, angina pectoris
  • Neutropenia - the leukocyte count may be high or
    low, but neutropenia is characteristic
  • Unexplained fever, serious infections
  • Thrombocytopenia
  • Bruising, petechiae
  • Less common lymphadenopathy, splenomegaly, skin
    infiltration, chloromas (tumors composed of
    malignant marrow cells)

5
Acute Leukemia
  • Diagnosis gt20 blasts in the bone marrow
  • Categorized by
  • HE staining
  • Cytochemical stains (myeloperoxidase, NSE)
  • Flow cytometry
  • 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
  • Incidence 10/100,000 per year in those
  • gt 60 years of age
  • 9700 cases per year in USA
  • Prognosis
  • Untreated - six weeks
  • With treatment - median survival 18 months
  • Some long term survivors

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

9
ANLL - FAB Classification
  • M0 Undifferentiated leukemia
  • MI AML without maturation
  • M2 AML with maturation
  • M3 Acute promyelocytic leukemia
  • M4 Acute myleomonoblastic leukemia
  • M5 Acute monoblastic leukemia
  • M6 Erythroleukemia
  • M7 Megakaryoblastic 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
  • goal to ablate abnormal clone and achieve a
    complete remission (CR)
  • CR normal blood counts with no increase in
    marrow blasts.
  • Chance of CR 60-85

19
Acute Promyelocytic Leukemia
  • Associated with a 1517 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
  • With consolidation, 20-40 may be long-term
    survivors
  • 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 gt 100 x 109/L
  • Complex karyotype
  • Age gt 60
  • Need for mechanical ventilation

23
Some Important Translocations in Leukemia
  • 1517 translocation seen in acute promyelocytic
    leukemia.
  • 821 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-2 10-19 blasts

29
Myelodysplastic syndromes FAB WHO
Classification
  • Refractory anemia (lt5 blasts)
  • Refractory anemia with ringed sideroblasts (RARS)
  • RCMD with ringed sideroblasts (RSCMD)
  • Refractory anemia with excess blasts (RAEB)
  • RAEB-1 5-9 blasts
  • RAEB-2 10-19 blasts

30
Myelodysplastic syndromes FAB WHO
Classification
  • Refractory anemia (lt5 blasts)
  • Refractory anemia with ringed sideroblasts (RARS)
  • RCMD with ringed sideroblasts (RSCMD)
  • Refractory anemia with excess blasts (RAEB)
  • RAEB-1 5-9 blasts
  • RAEB-2 10-19 blasts

31
Myelodysplastic syndromes WHO classification
  • Refractory anemia lt5 blasts
  • Refractory anemia
  • Refractory cytopenias with multilineage dysplasia
    (RCMD)
  • MDS with isolated del (5q-)
  • MDS-unclassified (MDS-U)
  • Refractory anemia with ringed sideroblasts (RARS)
  • RCMD with ringed sideroblasts (RSCMD)
  • Refractory anemia with excess blasts (RAEB)
  • RAEB-1 5-9 blasts
  • RAEB-2 10-19 blasts

32
MDS IPSS score
  • Score predicts prognosis
  • Features to be scored
  • Marrow blasts
  • Karyotype
  • Number 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 gt30
  • Platelet transfusions - give when platelets lt10 x
    109/L, or when at high bleeding risk
  • Antibiotics - empiric antibiotics with fever
  • Growth factors

35
Acute Lymphoblastic Leukemia (ALL)
  • Age Children (75 lt 6 years of age)
  • less common in adults
  • 3200 cases/year
  • Prognosis
  • Potential for cure is high in children
  • long term remissions possible in adults
  • Treatment
  • Induction therapy vincristine prednisone
    other agents
  • Consolidation and maintenance therapy
  • 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
  • B cell phenotype
  • Leukocyte count gt 100 x 109/L
  • Time to remission gt 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)
  • Bone marrow transplant
  • 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
  • 922 translocation yields a chimeric gene termed
    bcr-abl
  • bcr derived from chromosome 22
  • 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
Band
PMN
Eosinophil
Early Myeloid Cells
Basophil
Chronic Myelogenous Leukemia
45
BCR-ABL translocation
Chronic Myelogenous Leukemia
46
Chronic Myelogenous Leukemia
  • 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
  • Leukocyte count gt 200 x 109/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 gt 60 with allogeneic BMT
  • lt 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
  • Probably not a cure, but a remarkable advance
  • 87 major genetic response in chronic phase
  • 55 response in blast crisis
  • Alpha-interferon
  • 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
Chronic Lymphocytic Leukemia
  • Clonal proliferation of lymphocytes
  • -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
  • thrombocytopenia
  • unsightly adenopathy
  • 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
Hairy Cell Leukemia
  • 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 585-0255
  • Pager 339-5214
  • email john.ward_at_hsc.utah.edu

59
(No Transcript)
60
Lymphoma Classification
  • I. Good Ones. (include nonconvoluted diffuse
    centrilobulated histioblastoma, immune
    binucleolar hyperbolic folliculated
    macrolymphosaracoma, T2-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 pseudoquasihistioly
    mphosarcomyleoblastoma, IgG variant of fragmented
    plasmatic gammopathy, triconvoluted ipsilateral
    rhomboid fever, Armours hyperthermic caninoma,
    and Hohners 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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