Leukemia

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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 Cancer Institute

Fall, 2005
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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.

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Leukemia

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

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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)

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Acute Leukemia

• Diagnosis gt20 blasts in the bone marrow
• Categorized by
• HE staining
• Cytochemical stains (myeloperoxidase, NSE)
• Flow cytometry
• Cytogenetics

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Acute Leukemia

• No evidence of maturation within blood or marrow
  

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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

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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.

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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

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Myeloblasts
Acute Myelogenous Leukemia
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Acute Myelogenous LeukemiaAuer Rod
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Blasts
Acute Myelogenous Leukemia with differentiation
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Promyelocyes
Acute Promyelocytic Leukemia
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Acute Monoblastic Leukemia
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Acute Myelomoncytic Leukemia
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ANLL - Clinical Correlates

• M3 disseminated intravascular coagulation
• M4, M5 skin gum infiltration hypokalemia
• M7 acute myelofibrosis

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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

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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

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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

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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

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ANLLRole 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

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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

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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

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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

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Myelodysplastic syndromesFAB 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)

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Myelodysplastic syndromesFAB WHO
Classification

• RA
• RARS
• RAEB
• RAEBIT
• CMML

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Myelodysplastic syndromesFAB WHO
Classification

• RA
• RARS
• RAEB
• RAEBIT now AML
• CMML now in myelodysplastic/myeloproliferative
  disease

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Myelodysplastic syndromesFAB WHO
Classification

• RA
• RARS
• RAEB
• RAEB-1 5-9 blasts
• RAEB-2 10-19 blasts

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Myelodysplastic syndromesFAB 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

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Myelodysplastic syndromesFAB 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

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Myelodysplastic syndromesWHO 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

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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

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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

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ANLLSupportive 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

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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

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Acute Lymphoblastic Leukemia
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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

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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

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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

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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

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Chronic Myelogenous Leukemia

• Age adults
• Prognosis 3-4 years without BMT, cures possible
  with BMT
• Treatment
• Imatinib (Gleevec)
• Bone marrow transplant
• Hydroxyurea /- interferon

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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)

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Chronic Myelogenous LeukemiaPhiladelphia
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

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Band
PMN
Eosinophil
Early Myeloid Cells
Basophil
Chronic Myelogenous Leukemia
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BCR-ABL translocation
Chronic Myelogenous Leukemia
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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

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Chronic Myelogenous LeukemiaResults 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

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Chronic Myelogenous LeukemiaOther 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

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Chronic Lymphocytic Leukemia

• Age the elderly
• Prognosis may live for many years even without
  treatment
• Treatment Watchful waiting, purine nucleoside
  analogues (fludarabine), alkylators

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Lymphocytosis
Chronic Lymphocytic Leukemia
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Chronic Lymphocytic Leukemia

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

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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
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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
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Hairy Cell Leukemia

• Age adults
• Prognosis many years
• Treatment Adenosine deaminase inhibitors
  (cladribine)

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

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Questions?Feel free to contact me

• Office 2141, Huntsman Cancer Institute
• Office phone [phone]
• Pager 339-5214
• email john.ward_at_hsc.utah.edu

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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

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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

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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

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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