4. HDS Multisystem > Leukemia > Flashcards

Leukemia Flashcards

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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

Study These Flashcards
A

Based on morphology.

23
Q

Acute Lymphoblastic Leukemia (ALL)

WHO Classification

Study These Flashcards
A

Genetic/molecular based system.

24
Q

B-cell Acute Lymphoblastic Leukemia (B-ALL)

Translocations

Study These Flashcards
A

Fusions w/ chimeric protein expression:

  • t(9;22) → BCR-ABL
  • t(12;21) → ETV-6-RUNX1
  • 11q23 → KMT2A (MLL)
25
T-cell Acute Lymphoblastic Leukemia (T-ALL) Translocations
Juxtaposition of a proto-oncogene to TCR ⇒ _over-expression of a normally silent gene_ **t(1;14)** → BCL9-IGH
26
Lymphoblastic Lymphoma (LBL) Overview
* **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
**ALL** vs **LBL**
28
Acute Lymphoblastic Leukemia (ALL) Clinical Presentation
* 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
Acute Lymphoblastic Leukemia (ALL) Initial Work-up
* _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
Acute Lymphoblastic Leukemia (ALL) Diagnostic Evaluation
* _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
Acute Lymphoblastic Leukemia (ALL) Peripheral Blood Evaluation
* Immature blasts are lymphocyte-like * Minimal cytoplasm * Nucleoli present * Larger than RBCs
32
Acute Lymphoblastic Leukemia (ALL) Bone Marrow Examination
**Marrow almost completely replaced by abnormal cells**
33
Acute Lymphoblastic Leukemia (ALL) Immunophenotypic Markers
34
Acute Lymphoblastic Leukemia (ALL) Prognostic Features
* **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
Acute Lymphoblastic Leukemia (ALL) Treatment Overview
**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
Acute Lymphoblastic Leukemia (ALL) Treatment in Children
* **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
Acute Lymphoblastic Leukemia (ALL) Treatment in Adults
* **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
Myeloproliferative Neoplasms
* 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
Chronic Myeloid Leukemia (CML) Overview
* **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
Chronic Myeloid Leukemia (CML) Diagnosis
**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
Chronic Myeloid Leukemia (CML) Clinical Course
**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
Chronic Myeloid Leukemia (CML) Blood Smear
Numerous different types of granulocytes at different stages of maturation
43
Chronic Myeloid Leukemia (CML) Therapeutic Options
**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
Imatinib mesylate | (Gleevac)
* 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
Small Lymphocytic Lymphoma/ Chronic Lymphocytic Leukemia (SLL/CLL) Overview
* **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
CLL Presentation
* **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
CLL Diagnosis
* _Peripheral blood flow cytometry_ * **⊕ for CD19, CD20, CD23** * **⊖ CD10** * **CD5 usually ⊕** * Bone marrow biopsy is not required
48
CLL Prognosis
_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
CLL Management
* 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
Chronic Lymphocytic Leukemia (CLL) Peripheral Blood Smear
**Numerous mature lymphocytes** **About the size of RBCs**
51
Hairy Cell Leukemia Overview
* 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
Hairy Cell Leukemia Clinical Presentation
Typical presenting symptoms: * **Pancytopenia** w/ infection, bleeding, etc * Can see a monocytopenia * **Splenomegaly**, usually massive
53
Hairy Cell Leukemia Diagnosis
* _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
Hairy Cell Leukemia Management
* **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
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