The Leukemias

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The Leukemias

• Sherron R. Helms, M.D.
• March 24, 2005

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Leukemias

• Proliferation of abnormal clone of hematopoietic
  cells
• Poor response to normal regulatory signals
• Diminished capacity for differentiation
• Ability to expand at expense of normal cells
• Ability to suppress growth of normal cells

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Leukemias- Etiology

• Generally unknown
• Host susceptibility- DNA repair mechanisms, Down
  syndrome
• Chromosomal damage- physical (XRT) or chemical
  (alkylating agents, benzene)
• Viral- EBV in Burkitt, HTLV-I in T cell ALL

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Leukemias- Diagnosis

• Generally requires bone marrow biopsy and
  aspirates with flow cytometry and cytogenetics
• CLL can be reliably diagnosed by flow cytometry
  on peripheral blood
• There must be gt 20 blasts in marrow for
  diagnosis of acute leukemia

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Leukemias- Classification

• Acute vs Chronic
• Based on natural history of the untreated disease
• Myeloid vs Lymphoid
• Based on the primary cell line involved

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Leukemias

• Lymphoid
• CLL
• ALL
• Myeloid
• CML
• AML

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Chronic Lymphocytic Leukemia
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CLL

• Relatively indolent clonal lymphoid disease
• Primarily B cell
• Includes Hairy Cell Leukemia
• Most common leukemia in adults
• Median age at diagnosis 62 y
• Etiology unknown
• Morphology Normal B cells

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CLL- Molecular Biology

• Normal appearance, abnormal function
• CD 5 expression
• Defective apoptosis
• Overexpression of bcl-2 gene

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CLL- Clinical Presentation

• Asymptomatic
• Lymphocytosis noted on routine CBC
• Lymphadenopathy and/or splenomegaly in 50 at
  diagnosis
• Staph, Strep, Herpes infections common
• Autoimmune hemolytic anemia in 10
• ITP in 2

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CLL- Immune dysfunction

• CLL B cells produce reduced levels of
  immunoglobulin in response to antigenic stimuli
• Quantitative and qualitative abnormalities in B,
  T, NK cells
• Impaired complement activation

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CLL- Staging

• LOW RISK
• Lymphocytosis only
• Average survival gt10 yrs
• INTERMEDIATE RISK
• Adenopathy and/or splenomegaly
• Average survival 7 yrs
• HIGH RISK
• Anemia and/or thrombocytopenia
• Average survival 1.5 yrs

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CLL- Clinical course

• Generally, indolent with gradual increase in
  lymphocytosis, adenopathy, splenomegaly. May be
  years before Rx required
• Richter syndrome- 5 transform to aggressive
  large cell lymphoma/leukemia
• Develop fever, weight loss, worsening anemia
  thrombocytopenia, rising lymphocyte count
• Short survival, poor response to therapy

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CLL- Treatment

• No survival advantage to therapy at time of
  diagnosis in low risk patients
• Indications for therapy
• B symptoms
• AIHA, ITP (steroids)
• Massive hepatosplenomegaly
• Bulky adenopathy
• Recurrent infections

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CLL- Treatment Options-I

• Chlorambucil- Oral alkylator, 50 RR, rare
  complete response
• Fludarabine- IV purine analog, 70 RR, 30 CR,
  prolonged T cell suppression
• IVIG Only in pts with repeated bacterial
  infections

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CLL- Treatment Options-II

• Monoclonal Antibodies
• Rituximab- antiCD20 when combined with chemo,
  95 RR, 68 CR
• Alemtuzumab- antiCD52- effective in clearing
  blood and marrow less effective on nodes.
  Prolonged, severe T cell suppression
• Bone Marrow Transplantation- autologous and
  allogeneic under study for healthy pts under 70yo

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Hairy Cell Leukemia

• Male predominance
• Cytopenias, splenomegaly
• Therapy Cladribine- nucleoside analog
• Single course of therapy
• 90 response rate
• Responses very durable
• Resistant disease- BL-22 MoAb antiCD22
  pseudomonas exotoxin induces apoptosis- 75 RR in
  clinical trials

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Acute lymphocytic leukemia
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Acute lymphoblastic leukemia

• Malignant disease of early B and T cells
• Aberrant differentiation and proliferation
• Cells accumulate in marrow and suppress normal
  hematopoiesis
• In addition to marrow and peripheral blood,
  involves nodes, liver, spleen, CNS, and skin

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A.L.L.

• 20 of adult leukemia
• Most common malignant disease in childhood
• Symptoms fatigue, fevers, bone pain, infection,
  bleeding, adenopathy
• CNS involvement in 5-10
• Blasts in peripheral blood in 90
• Leukostasis uncommon even with WBC 100,000

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A.L.L. Treatment

• Induction, consolidation, maintenance
• Use multiple chemotherapy agents to prevent
  resistance (vincristine, prednisone,
  daunorubicin, asparaginase)
• Use prophylactic Rx of CNS (intrathecal
  methotrexate and AraC)
• Postremission chemo to eliminate minimal residual
  disease
• Adults 65-90 remission 20-30 cure
• Allogeneic transplants in high risk pts

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Acute Myelogenous Leukemia
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A.M.L.

• Most common acute leukemia in adults
• Median age at diagnosis 60 yrs
• The most common type of leukemia induced by
  alkylating agents (nitrogen mustard 7y) or
  epipodophyllins (VP16, 1-2 y)

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AML

• Auer rods accumulation of lysosomal granules in
  cytoplasm, seen in 10
• Diagnosis by flow cytometry, cytogenetics on
  marrow
• FAB classification has 8 subtypes (M0- M7) WHO
  classification has 19

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AML- Clinical Features

• Presenting symptoms fatigue, bruising, infection
• Acute promyelocytic subtype presents with
  bleeding, sometimes frank DIC
• Acute myelomonocytic subtype often has gum and/or
  skin involvement
• Leukostasis (pulm and CNS) common when blast
  count gt50,000

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A.M.L.- Therapy

• Remission induction with cytarabine and
  daunorubicin
• all-trans retinoic acid (ATRA) is added in acute
  promyelocytic leukemia (APL)
• Postremission consolidation chemo using high
  dose cytarabine for 2 cycles
• 40 cure rate in young and middle aged adults
• Maintenance therapy only in APL (ATRA)
• Allogeneic transplant in high risk pts lt70y who
  have match and are in CR

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AML in Elderly

• Poorer outcome, 10 long term survivors
• Less able to withstand intensive chemotherapy and
  complication of prolonged marrow suppression
• Less marrow regenerative capacity
• More often have poor-prognosis subtypes of
  leukemia
• More often have MDS evolving into AML, multiple
  mutations and drug resistant

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Acute Promyelocytic Leukemia (APL)

• M3 subtype of AML
• Promyelocytes contain granules with procoagulant
  and fibrinolytic activity
• t(1517) juxtaposes the RARa gene on 17 with the
  PML gene on 15
• The resulting PML/RARa represses transcription of
  the RAR needed for differentiation/apoptosis
• High doses of ATRA cause release of the
  corepressor

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A.P.L.

• Retinoic acid standard chemotherapy with
  daunorubicin and cytosine arabinoside (AraC)
• 95 remission rate, 70 cure rate
• Arsenic trioxide active in relapsed disease
  (causes histone acetylation, differentiation,
  apoptosis)

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Chronic Myelogenous Leukemia
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Chronic Myelogenous Leukemia

• A myeloproliferative disorder (CML, P. Vera,
  E.T.)
• Clonal disorder of pluripotential stem cell
• Median age 45-55 yrs
• Philadelphia chromosome t(922) in 95

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CML

• Expansion of myeloid cells at various stages of
  maturation
• Three clinical phases chronic, accelerated, and
  blast crisis
• Patients proceed through these phases over 4yrs
  if untreated
• Symptoms fatigue, night sweats, sx related to
  splenomegaly
• High WBC, increased basophils, high platelet
  count

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Ph Chromosome

• BCR-ABL protein product of the translocation
• Transfection of BCR-ABL in mice causes CML
• Inhibition of BCR-ABL in patients reverses CML
• Acquired disorder
• Cause of mutation unknown- radiation in some

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Ph Chromosome- BCR-ABL

• Tyrosine kinase activity
• Leads to increased transcription of genes that
  control cell proliferation
• Inhibits expression of cell adhesion molecules
• Suppresses apoptosis

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CML- Treatment

• The BCR-ABL proteins must be phosphorylated to
  have tyrosine kinase activity
• Imatinib (Gleevec) blocks phosphorylation
• Oral agent, well tolerated
• 87 RR, 76 complete cytogenetic response
• Allogeneic stem cell transplant cures 75 of pts
  under age 70

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