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4. HDS Multisystem > Leukemia > Flashcards

Leukemia Flashcards

1
Q

Acute Leukemia

A
  • Group of hematologic malignancies
  • Characterized by proliferation of immature hematopoietic elements (blasts) and maturation arrest
  • Leukemia initiating cell has self-renewal properties (leukemia stem cell)
  • Can be myeloid, lymphoid, or (rarely) biphenotypic
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2
Q

Leukemogenic

Events

A
  • DNA damage ⇒ ionizing radiation, chemicals, chemotherapeutic agents
  • Inherited factors ⇒ possibly through loss of tumor suppression genes, Down syndrome
  • Virus infections ⇒ HTLV-I associated w/ adult T-cell leukemia/lymphoma
  • Abnormal immune response to infection ⇒ ETV6/RUNX1 in childhood ALL (acute lymphoblastic leukemia)
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3
Q

Differentiation Block

A

Cells are no longer able to develop beyond the blast stage.

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4
Q

Proliferation Advantage

A
  • FLT3 = fms-like tyrosine kinase 3
  • Mutations ⇒ ligand independent autophosphorylation of the receptor
  • Results in constitutive activation
  • Present in about 30% of newly diagnosed cases of AML
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5
Q

Acute Leukemia

Pathophysiology

A
  • ↑ Blasts in blood and bone marrow
  • Replacement of normal hematopoietic elements ⇒ neutropenia, anemia, and thrombocytopenia
  • Malignant blasts can infiltrate extramedullary organs
    • Brain and testes ⇒ common in ALL
    • Skin and gums ⇒ common in AML
  • Hyperleukocytosis ⇒ presence of many myeloblasts causing obstruction of small arterioles in brain, eye, lung
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6
Q

Acute Leukemia

WHO Classification

A
  • By definition:
    • Blasts > 20% of the bone marrow or peripheral WBC differential count
  • Two main categories:
    • Acute Myeloid Leukemia
    • Acute Lymphoblastic Leukemia
  • Morphology is not always reliable to distinguish myeloid from lymphoid
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7
Q

Myeloblasts

Morphology

A
  • Auer rod ⇒ abnormal azurophilic granules that have formed crystals
  • Indicates myeloid differentiation & AML
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8
Q

Acute Leukemia

Immunohistochemical Evaluation

A

ALL “PAS”

AML is a MES

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9
Q

Acute Leukemia

Immunophenotyping

A

Based on flow cytometry:

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10
Q

Acute Myeloid Leukemia (AML)

Overview

A
  • Arises from myeloblastic stem cells
  • 1% of all cancers
  • Median age 68
  • Can arise de novo
  • Can arise secondary to chemotherapy or another bone marrow disorder
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11
Q

Acute Myeloid Leukemia (AML)

FAB Classification

A

Based on morphology:

Know M3, M4, M5

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12
Q

Acute Myeloid Leukemia (AML)

WHO Classification

A

Based on recurrent genetic abnormalities, etiologies, and morphology:

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13
Q

Acute Myeloid Leukemia (AML)

Presenting Symptoms

A
  • Infections (low neutrophils)
    • PNA
    • Cellulitis
    • Usu. not URI’s
  • Bleeding (low platelets)
  • Fatigue (low Hb)
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14
Q

Acute Myeloid Leukemia (AML)

Initial Work-up

A
  • Physical exam:
    • Unlike ALL, there is generally no lymphadenopathy or organ involvement
  • Labs:
    • CBC w/ diff; peripheral smear; coags; type and cross;
    • Uric acid, Ca, PO4, Cr, K
  • Flow cytometry (peripheral blood vs bone marrow)
  • Bone marrow biopsy
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15
Q

Acute Myeloid Leukemia (AML)

Diagnostic Evaluation

A
  • Morphology
    • Abnormal hypercellular bone marrow
  • Cytochemical staining
    • PAS ⊖
    • ⊕ for MPO, SBB, Nonspecific esterase
  • Immunophenotype
    • Flow cytometry: Myeloid antigens
      • ⊕ for CD34, CD13, CD33, and CD117
  • Cytogenetics
  • Molecular studies
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16
Q

Acute Myeloid Leukemia (AML)

Prognosis

A
  • Two factors determine prognosis:
  • Age
    • Younger = better
    • Prognosis for pts > 60 years old remains poor
  • Cytogenetic abnormalities
    • t(15;17) ⇒ Acute Promyelocytic Leukemia (APL) ⇒ very good prognosis
    • t(8;21) / t(16;16) / inv(16) ⇒ Core Binding Factor AML ⇒ good prognosis
    • No abnormalities ⇒ intermediate prognosis
    • del(7) / 11q23 (KMT2A) / multiple abnormalities ⇒ poor prognosis
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17
Q

Acute Promyelocytic Leukemia (APL)

Characteristics

A
  • Associated w/ t(15;17) translocation
  • Highly curable
  • Often presents w/ DIC (but also can present w/ thrombosis)
  • Treated w/ chemotherapy fee regimens
    • All trans-retinoic acid (ATRA) and Arsenic trioxide (ATO)
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18
Q

Monocytic Leukemias

Characteristics

A
  • Often present w/ leukocytosis as opposed to leukopenia
  • Risk for leukostasis ⇒ symptomatic hyperleukocytosis
  • (typically blasts > 50K)
    • Hypoxic respiratory failure
    • Stroke
    • Tissue infiltration
    • Gingival hyperplasia
    • Leukemia cutis
    • CNS involvement
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19
Q

Risk-Adapted Treatment

Principles

A
  • Pts w/ best prognosis receive least intense treatment
    • ↓ Risk of treatment induced mortality
    • Ex. APL [t(15;17)] ⇒ Chemotherapy-free utilizing all trans retinoic acid and arsenic trioxide
  • Pts w/ worst prognosis receive most intense treatment
    • ↓ Reduce relapse risk
    • Intermediate/Poor risk ⇒ Induction chemotherapy and consolidation transplant
    • Ex. CBF leukemia ⇒ Induction and consolidation chemotherapy
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20
Q

Multi-Agent Chemotherapy

Adverse Effects

A
  • Mucositis
  • Alopecia
  • Pancytopenia ⇒ infection risk
  • In children ⇒ growth retardation
  • In young adults ⇒ amenorrhea in women, infertility in men and women
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21
Q

Acute Lymphoblastic Leukemia (ALL)

Characteristics

A
  • Most common childhood malignancy
  • Peak age of 2-4 years in industrialized countries
  • More common in Hispanics and Caucasians than African Americans
  • Slightly more common in males than female
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22
Q

Acute Lymphoblastic Leukemia (ALL)

FAB Classification

A

Based on morphology.

23
Q

Acute Lymphoblastic Leukemia (ALL)

WHO Classification

A

Genetic/molecular based system.

24
Q

B-cell Acute Lymphoblastic Leukemia (B-ALL)

Translocations

A

Fusions w/ chimeric protein expression:

  • t(9;22) → BCR-ABL
  • t(12;21) → ETV-6-RUNX1
  • 11q23 → KMT2A (MLL)
25
Q

T-cell Acute Lymphoblastic Leukemia (T-ALL)

Translocations

A

Juxtaposition of a proto-oncogene to TCR ⇒ over-expression of a normally silent gene

t(1;14) → BCL9-IGH

26
Q

Lymphoblastic Lymphoma (LBL)

Overview

A
  • Morphologically and immunophenotypically indistinguishable from ALL
  • Distinction is based on:
    • Site of disease
    • Amount of bone marrow involvement
      • 20% lymphoblasts in the bone marrow ⇒ ALL
      • < 20% lymphoblasts in the bone marrow w/ extramedullary manifestations ⇒ LBL
  • Management is similar for both
27
Q

ALL vs LBL

A
28
Q

Acute Lymphoblastic Leukemia (ALL)

Clinical Presentation

A
  • Fever, pallor, fatigue
  • Organomegaly (30-50 % w/ HSM)
  • Adenopathy
  • Bone pain, limp, arthritis (40 %)
  • Headache, cranial nerve palsy
  • Prolonged “viral illness”
  • Bruising, petechiae, bleeding
29
Q

Acute Lymphoblastic Leukemia (ALL)

Initial Work-up

A
  • Physical exam:
    • Head to toe, w/ emphasis on testes, CNS, lymphadenopathy, organomegaly
      • Testicles and CNS are termed sanctuary sites
      • Difficult for chemotherapy to reach
  • Labs:
    • CBC w/ diff; peripheral smear; coags; type and cross;
    • Uric acid, Ca, PO4, Cr, K
  • Flow cytometry (peripheral blood vs bone marrow)
  • Bone marrow biopsy
30
Q

Acute Lymphoblastic Leukemia (ALL)

Diagnostic Evaluation

A
  • Morphology
  • Cytochemical staining
    • ⊕ PAS
    • ⊖ MPO, SBB, Nonspecific esterase
  • Immunophenotype
  • Flow cytometry: B-cell or T-cell antigens
  • Cytogenetics
    • Ig and TCR gene rearrangement studies
31
Q

Acute Lymphoblastic Leukemia (ALL)

Peripheral Blood Evaluation

A
  • Immature blasts are lymphocyte-like
  • Minimal cytoplasm
  • Nucleoli present
  • Larger than RBCs
32
Q

Acute Lymphoblastic Leukemia (ALL)

Bone Marrow Examination

A

Marrow almost completely replaced by abnormal cells

33
Q

Acute Lymphoblastic Leukemia (ALL)

Immunophenotypic Markers

A
34
Q

Acute Lymphoblastic Leukemia (ALL)

Prognostic Features

A
  • CNS disease (20%)
    • Higher risk of relpase
  • Early response to therapy
    • Morphologic: Rapid early responders do better
      • Obtaining remission by day 14, with ⊖ MRD by day 28
    • Measurable residual disease (MDR)
      • Measurement of very low levels (1 in 1000) of leukemic cells by PCR
      • High MRD at the end of induction ⇒ higher risk of relapse
35
Q

Acute Lymphoblastic Leukemia (ALL)

Treatment Overview

A

Children ⇒ > 95% achieve remission and 80% are cured

Adults ⇒ 65-85 %achieve remission w/ cure rates of 35-40%

  • What made the difference?
    • Development of complex chemotherapeutic regimens
    • Improvements in supportive care
    • Recognition of CNS as sanctuary site
    • Risk adaptive therapy
    • Bone Marrow Transplant for highest risk pts
36
Q

Acute Lymphoblastic Leukemia (ALL)

Treatment in Children

A
  • Induction (3 or 4 drug): 95% will achieve remission
  • Consolidation
  • Interim maintenance
  • Delayed intensification
  • Maintenance (to complete 2 years of therapy for girls, 3 years of therapy for boys)
  • High-risk ⇒ allogeneic transplant
    • Refractory disease
    • MRD positive
    • Poor-risk
37
Q

Acute Lymphoblastic Leukemia (ALL)

Treatment in Adults

A
  • Induction (Hyper CVAD, pediatric regimen, etc)
    • Vincristine, Steroids, Cytoxan and Anthracycline
  • Consolidation
    • High dose Cytarabine, Cytoxan, Methotrexate, Asparaginase
    • SCT may be used
  • Maintenance (2-3 years)
    • 6-MP, Methotrexate, monthly steroids, and Vincristine
  • CNS Prophylaxis
  • High-risk ⇒ allogeneic transplant
38
Q

Myeloproliferative Neoplasms

A
  • Group of (mostly) clonal hematologic disorders
  • Characterized by accumulation of mature cells
  • Accumulation can involve one or more cell lines
  • No age, sex or race predilection
  • Rare disorders w/ collective annual incidence of 5/100,000
39
Q

Chronic Myeloid Leukemia (CML)

Overview

A
  • Most common in middle-aged adults
  • Clinical signs and symptoms include:
    • Leukocytosis w/ left-shift (often in asymptomatic individuals)
    • Basophilia
    • Elevated LDH and uric acid
    • Splenomegaly
40
Q

Chronic Myeloid Leukemia (CML)

Diagnosis

A

Dx can be confirmed by demonstration of the t(9;22) by:

  • Karyotyping
  • Fluorescent In-Situ Hybridization (FISH)
  • BCR-ABL mRNA by PCR

Although dx of CML requires demonstration of t(9;22), not all diseases w/ t(9;22) are CML.

41
Q

Chronic Myeloid Leukemia (CML)

Clinical Course

A

t(9;22) is both sufficient and required to develop CM

Disease goes through three phases:

  • Chronic phase ⇒ ↑ WBC w/ left shift
    • Typically remains stable for 3-4 years (up to 10 years)
    • Pts generally have no or minimal sx
    • W/o treatment median survival is 5-7 years
    • Disease inevitably will progress to accelerated phase and blast crisis
  • Accelerated phase ⇒ Additional cytogenetic abnormalities, uncontrollable WBC, ↑ basophilia
    • Median survival w/o treatment is 12-18 months
  • Blast phase (acute leukemia)
42
Q

Chronic Myeloid Leukemia (CML)

Blood Smear

A

Numerous different types of granulocytes at different stages of maturation

43
Q

Chronic Myeloid Leukemia (CML)

Therapeutic Options

A

Allogeneic stem cell transplantation

  • Only tx modality w/ curative potential
  • Cure rates vary
    • 80%+ for young (<40 years) pts w/ an HLA-identical sibling donor
    • 40% for elderly pts undergoing a matched-unrelated donor transplant
    • Cure rates are much worse for pts transplanted in accelerated phase (40%) or blast crisis (20%)
    • Somewhat worse for pts transplanted > 1 year after diagnosis
44
Q

Imatinib mesylate

(Gleevac)

A
  • Novel therapeutic options for CML (“targeted therapy”)
  • Tyrosine kinase inhibitor
    • Occupies ATP binding site in BCR-ABL oncoprotein ⇒ ⊗ of BCR-ABL tyrosine kinase activity
  • Side effects are minimal
  • Treatment-of-choice for most pts w/ CML in chronic phase
    • 65% of pts in chronic phase will achieve a sustained (> 7 years) complete cytogenetic response w/ imatinib
      • No Ph chromosome on cytogenetic exam
    • 30-40% of pts will not have e/o BCR-ABL transcript by PCR
      • BCR-ABL fusion gene presence can still be demonstrated in isolated ‘stem’ cells
45
Q

Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia (SLL/CLL)

Overview

A
  • Lymphoma / leukemia composed of small clonal B-cells
  • M > F, Age > 50 yrs
  • Considered low grade, but incurable
  • SLL and CLL are morphologically, phenotypically, and genotypically indistinguishable
    • Differ only in degree of peripheral blood lymphocytosis
      • 5K WBCs regardless of lymphadenopathy ⇒ CLL
      • < 5K WBCs ⇒ SLL
  • SLL is 7% of NHL
  • CLL is the most common leukemia in western world
46
Q

CLL

Presentation

A
  • Mostly asymptomatic
    • Often identified on routine blood work w/ isolated lymphocytic leukocytosis
  • ± Recurrent respiratory infections due to hypogammaglobulinemia
  • ± Immunologic issues such as hemolytic anemia or immune thrombocytopenic purpura
47
Q

CLL

Diagnosis

A
  • Peripheral blood flow cytometry
    • ⊕ for CD19, CD20, CD23
    • ⊖ CD10
    • CD5 usually ⊕
  • Bone marrow biopsy is not required
48
Q

CLL

Prognosis

A

Prognostic studies include:

  • FISH
    • del(13q) = good
    • del(17p) = bad
    • IGHV mutation (immunoglobulin heavy chain variable region)
      • Presence is favorable
      • Absence is unfavorable
  • Next-generation sequencing (NGS)
    • TP53 mutation is unfavorable
49
Q

CLL

Management

A
  • Unless presence of sx from compressive LNs or splenomegaly or severe cytopenias then observation is preferred
  • Treatment, if required, is dependent on risk-stratification and age:
    • Chemoimmunotherapy
      • Fludarabine, cyclophosphamide, rituximab (FCR)
      • Bendamustine, rituximab (BR)
      • BTK Inhibitors
      • Ibrutinib
      • Acalabrutinib
50
Q

Chronic Lymphocytic Leukemia (CLL)

Peripheral Blood Smear

A

Numerous mature lymphocytes

About the size of RBCs

51
Q

Hairy Cell Leukemia

Overview

A
  • Considered a chronic B-cell lymphoproliferative disorder
    • Initially described as leukemic reticuloendotheliosis
  • Bone marrow infiltration by atypical lymphocyte w/ “hairy” projections
  • Characterized by splenomegaly, pancytopenia
  • 4:1 male to female ratio
  • Usu. 40-60 y/o
52
Q

Hairy Cell Leukemia

Clinical Presentation

A

Typical presenting symptoms:

  • Pancytopenia w/ infection, bleeding, etc
    • Can see a monocytopenia
  • Splenomegaly, usually massive
53
Q

Hairy Cell Leukemia

Diagnosis

A
  • Bone marrow biopsy
    • Bone marrow infiltration by atypical lymphocyte w/ “hairy” projections and indistinct cytoplasmic border
    • Stains w/ TRAP = tartrate resistant acid phosphatase ⊕
  • Immunophenotype:
    • ⊕ for CD103, CD11c, CD25, CD22
    • ⊖ for CD5, CD10, CD23
  • Molecular
    • BRAF mutation
54
Q

Hairy Cell Leukemia

Management

A
  • Goal is long-term remission
  • Generally not considered curable w/ standard therapies
  • Therapy consists of chemotherapy ± immunotherapy
    • Nucleoside analogs – cladribine, pentostatin
    • Anti CD20 MoAb – Rituximab
    • Salvage targets
      • Vemurafenib (BRAF inhibitor)

4. HDS Multisystem (43 decks)

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