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HMS Homeostasis I > Acute Leukemias > Flashcards

Acute Leukemias Flashcards

1
Q

Important difference between acute leukemias and myeloproliferative neoplasms

A

Unlike the myeloproliferative neoplasms, acute leukemias have defects that block or significantly retard differentiation.

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2
Q

Many acute leukemias result from loss-of-function or functional knockdown of proteins that ___.

The major exception to this is ___.

A

Many acute leukemias result from loss-of-function or functional knockdown of proteins that initiate transcription programs for maturation of progenitor cells.

The major exception to this is NOTCH. NOTCH gain-of-function produces acute leukemia by driving proliferation and suppressing differentiation.

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3
Q

T-cell acute lymphoblastic leukemia/lymphoma

A

The disease that is specifically associated with NOTCH1 gain-of-function mutations in humans

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4
Q

A lone loss-of-function mutation in a hematopoietic transcription factor vital for differentiation is . . .

A

. . . necessary but insufficient to cause acute leukemia (with the notable exception of NOTCH1 GoF).

There must be other mutations that drive proliferation in addition to this lack of ability to differentiate.

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5
Q

Class 1 and class 2 acute leukemia mutations

A

Class 1: Drives proliferation

Class 2: Prevents differentiation

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6
Q

Most myeloproliferative disorders have class 1 mutations in . . .

A

. . . tyrosine kinases

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7
Q

Leukemia and MPD

A
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8
Q

Acute lymphoblastic leukemia

A

BCR-ABL / Philidelphia chromosome-driven leukemia of B cell origin

Same as in CML, except there is a slight difference.

ALL presents with a 190 kDa BCR-ABL fusion

CML presents with a 210 kDA BCR-ABL fusion

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9
Q

Ikaros

A

Transcription factor that regulates early stages of lymphocyte development.

The Ikaros mutations found in the blast crisis stage are absent from the preceding stable phase of CML, linking them directly to the transformation of the myeloproliferative neoplasm to acute leukemia.

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10
Q

B cell and T cell tumors

A

B-cell tumors almost always arise in the bone marrow (where B cells develop) and present as “leukemias,” whereas T-cell tumors often arise in the thymus (where T cells develop) and present as lymphomatous masses

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11
Q

Acute lymphoblastic leukemia

A
  • Most common hematologic malignancy of children
  • 10-15% of acute leukemia in general population
  • Two subdivisions: B-cell origin and T-cell origin
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12
Q

B-ALL

A
  • 85% of ALL cases
  • Peak incidence 3 years
  • White and Hispanic ethnicities and Down syndrome increase risk
  • Several weeks of fatigue due to anemia, bruising due to thrombocytopenia
  • Displacement of bone marrow by lymphoblasts, resulting in pancytopenia
  • May also involve meninges and sex organs
  • Splenomegaly, hepatomegaly, and lymphadenopathy common
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13
Q

Diagnosing B-ALL

A
  • Bone marrow biopsy
  • Lymphoblasts, cells with fine chromatin, small nucleoli, and scant agranular cytoplasm, cover at least 20% of the marrow cellularity
  • Definitive diagnosis requires immunophenotyping by flow
  • Positive for TdT and all B-cell lineages for CD19
  • Lesions of lymphocytic infiltrates on H and E will show all stages of B cell precursor, distinguishing them from mature B cell malignancies
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14
Q

What does this aspirate show?

A

B-ALL

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15
Q

Prognosis of B-ALL

A

Overall very good in children. Complete remission in >95% of cases, cures in 75-80% patients.

For adults, outcome is less favorable, with cures in ~50% of cases.

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16
Q

T-ALL

A

Peak incidence is 15 years, when thymus reaches its greatest size. Twice as common in males.

2/3 presents as mediastinal lymphoma, residing in the thymus (retrosternal radiopaqueness). Produces cough, shortness of breath, and SVC syndrome by compressing airways and SVC.

Remaining 1/3 presents as with bone marrow involvement with a picture nearly identical to B-ALL. T-ALL presenting in this way often produces organomegaly and neurological symptoms.

17
Q

Diagnosis of T-ALL

A
  • Based on morphologic demonsrtation of lymphoblasts in thymus and marrow
  • Immunophenotyping essential for diagnosis
  • Express T-cell markers, CD1a, CD3, and CD4 or CD8
  • Cytogenetics not as helpful as for B-ALL
  • NOTCH1 mutations quite common
  • Class 1 mutations largely unknown
  • LoF in CDKN2A common (inhibitor of CDK4)
18
Q

The below was taken from the thymus. What is the likely diagnosis?

A

T-ALL

19
Q

T-ALL on Flow

A
20
Q

Prognosis of T-ALL

A

75-80% of pediatric cases cured

~50% adult cases cured

21
Q

Treatment of ALL (T and B)

A
  • Very aggressive tumors with fast growth rates and high proclivity to infiltrate organs, treatment needed within weeks to months
  • High levels of intravenous and intrathecal chemotherapy to induce remission. Usually clear at ~4 weeks, as assessed by flow and PCR
  • Remission is consolidated with additional rounds of chemotherapy going out ~2.5 years
  • Supportive therapy: Red cell and platelet transfusions, careful monitoring for infection, meticulous attention to fluid, electrolyte, and acid-base status, psychological support for patient and family
  • Obviously, imatinib for BCR-ABL fusions
22
Q

Acute myeloid leukemia

A
  • Most common acute leukemia in adults
  • Risk factors: previous radiotherapy and certain chemotherapies, inherited DNA repair defects, inherited neutropenias (like elastase def), smoking, intercalator toxicity
  • Pre-existing myelodysplastic syndromes and myeloproliferative disorders have a risk of progressing to AML
  • Signs/symptoms of neutropenia, thrombocytopenia, and anemia
  • Rarely causes organomegaly, but commonly invades soft tissues like the gums
  • Patients may present with pulmonary and neuro symptoms due to cells sticking in capillaries
  • May cause DIC
23
Q

Diagnosing AML

A
  • Inspection of bone marrow and peripheral blood
  • histochemistry, immunophenotyping, and cytogenetics
  • Note that absence of blasts in the peripheral blood (so-called aleukemic leukemia) does not exclude the diagnosis​
  • Marrow usually hypercellular, but may appear normal
  • Increased # of blasts present (>20% of marrow)
  • Auer rods (pathognomonic for malignant myeloblasts)
  • Flow shows increased CD33, CD13, and CD117 and/or monocytic markers such as CD14.
24
Q

What is indicated by the asterisk on the left figure and what is the likely diagnosis?

A

Auer rods

Neoplasm of myeloblasts

25
Q

AML sometimes follows a course of ____.

A

AML sometimes follows a course of etoposide.

A topoisomerase II inhibitor antibiotic/chemotherapeutic

26
Q

Treatment of AML

A
  • Generally treated with high dose chemotherapy followed by additional cycles
  • HSC transplant sometimes employed
  • Targeted therapies under study
27
Q

Treatment of acute promyelocytic leukemia

A

May be treated with all-trans-retinoic acid! Usually with arsenic, which interferes with fusion protein. Puts patients into remission, but isn’t a total cure. Mostly used in combination with chemotherapy.

Retinoic acid forces differentiation of these cells into mature neutrophils, resulting in neutrophilia, but otherwise a reduction in symptoms.

Complications may arise from mass differentiation all at once, often manifesting as dyspnea and pulmonary exudate. These can be treated with corticosteroids.

28
Q

Acute Promyelocytic Leukemia

A

Caused by a single fusion event of RARa-PML

RAR is chr17, PML is chr 15. RAR is the retinoic acid receptor required to drive myeloid differentiation. Results in a receptor that is not sensitive to physiologic concnetrations of retinoic acid, but may be rescued by exogenous retinoic acid. Cells with large numbers of Auer rods are pathognomonic for APML.

Cells degranulate and result in hypercoagulability and DIC, as opposed to the typical pathology of pancytopenia.

29
Q

Key prognostics in AML

A

Note: Secondary AML has a much worse prognosis than primary

30
Q

Paradigm for non-AML leukemias

A
31
Q

Tumor Lysis Syndrome

A

Rapid lysis of many tumor cells results in release of their cytoplasmic contents into blood: Hyperkalemia, hyperuricemia, and hyperphosphatemia.

Hyperkalemia results in arrhythmias and hyperuricemia in renal problems, potentially renal failure. Renal failure may be prevented by administering allopurinol.

32
Q

Life-threatening complications of leukemia

A
  • Hematologic emergencies from effective pancytopenia
  • Tumor lysis syndrome
  • Leukostasis
  • Anterior mediastinal mass resulting in anatomic occlusions
  • Dissemianted intravascular coagulation
33
Q

Leukostasis

A

Occurs more in myeloid cancers than lymphoid cancers

HMS Homeostasis I (62 decks)

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