Heme - Aml And Mds

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Myelodysplastic syndrome

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Cells divide but mutate and thus don't mature normally.

One of the hallmarks is anemia! (macrocytic)

Can be suspected based on CBC. 1-2 or pan cytopenia.

No hepatosplenomegaly.

Thrombocytosis occurs in the 5q minus subset.

1/2 associated with cytogenetic abnormality.

Prevalence increases with age.

HALLMARK OF THIS DISORDER IS DYSPLASIA!

15% present with autoimmune disorders.

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MDS - Histopathology

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Neutrophils won't have enough lobes and granules.
Nucleated RBCs. Clustered/abnormal megakaryocytes in the marrow. Ringed sideroblasts seen with iron stain in the bone marrow.

BM will be hypercellular with single/multi-lineage dysplasia. Peripheral blood cytopenia due to intramedullary apoptosis.

Front 3

MDS progression

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If blasts exced 20% in marrow or blood, it is AML by definition!

(and an AML of poor prognosis, at that)

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Types of MDS

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De novo

Secondary (e.g. radiation, chemo, toxins)

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MDS scoring system (3 factors)

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Number of blasts in marrow

Number of cytopenias

Karyotype.


This score will give you median surv btwn 5.7 years and 5 months.

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Tx of MDS

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Once cytopenia develops, we treat the symptoms.

Supportive care (transfusions, antibiotics)

Growth factors (GCSD, EPO)

Immunomod agents

Chemo

Allogeneic transplant (the only curative therapy)

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Good prognosis MDSs

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Low risk of transformation to AML - 5q- (5q minus) syndrome

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Poor prognosis MDSs

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Complex cytogenetics (3 or more abnormalities) and changes in chrom 5 and 7 with exception of 5q- syndrome.

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Chronic myelomonocytic leukemia (CMML)

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Chronic myelodysplastic/myeloproliferativedisorder

Has proliferation of monocytes in periph blood AND dysplasia in one or more cell lines in the marrow.

Poor prognosis, along the lines of aggressive AML.

So it is a combo of MDS and a myeloproliferative disorders. get macrocytosis bc RBCs dont mature all the way.

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Acute vs. chronic myeloid leukemias

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Acute...
is immediately life threatening, patients are very ill at presentation, immature cells are found in periph blood and marrow (while maturing and immature cells found in PB and marrow for chronic), and marrow failure at presentation.

For acute, you must treat the patient within a week or two!

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Presenting signs/sx of AML

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Neutropenia (infection), anemia (fatigue and SOB) and thrombocytopenia (bleeding and bruising).

(PBL case)

may also see...DIC, bone pain, solid tumor of leukemia cells (granulocytic sarcoma or chloroma), cutaneous or gingival leukemic infiltration, organomegally and enlarged lymph nodes.

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Lab eval of AML

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Lots of blasts in the marrow (so you will see granules, Auer rods!!!).
Will stain positive for myeloperoxidase.

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Flow cytometry of AML

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Examines cell size, granularity and antigens.

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Flow cytometry of AML
Hematologic precursors (stem cells)

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CD34

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Flow cytometry of AML
B cell lineage

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CD19, CD20, CD22 (larger numbers)

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Flow cytometry of AML
T cell lineage

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CD3, CD4 (smaller numbers)

Front 17

Flow cytometry of AML
Myeloid

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CD33 (the 3s)

Front 18

Cytogenetics of AML

Good prognosis

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M2 - t(8;21) - ETO/AML1
M3 - Acute promyelocytic leukemia - APL - t(15;17). This is PML/RAR alpha translocation
M4Eo - Inv(16) - CBF beta split

80-90% overall survival.

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Cytogenetics of AML

Intermediate prognosis

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"includes normal cytogenetics")

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Cytogenetics of AML

Poor prognosis

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Chromosome 5 and 7 abnormalities (developing from MDS or secondary AMLs)

Complex cytogenetics (3 or more abnormalities)

Also CML that goes to AML. - t(9;22)

<10% survival. Most pts are in this category.

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Classification of AML

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FAB - Based on histology. M0-M7
WHO - Based on morphology, immunophenotype, cytogenetic-biologically homogenous entities. It is more clinically relevant.

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WHO categories for AML

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AML with recurrent cytogenetic abnormalities.
AML with t(8;21)-AML1/ETO
AML with inv(16)-CBFbeta/MYH11
AML with t(15;17)-PML/RARalpha

AML with multilineage dysplasia/AML with myelodysplasia-related changes

AML and myelodysplasia syndromes, therapy related

AML not otherwise classified

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M4

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acute myelomonocytic leukemia
Inv(16)
Good prognosis

Front 24

M2

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AML with maturation.
t(8;21)
good prognosis

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Auer rods

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Collection of pink granules in myeloblast. IN AML!

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Dx of AML

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BM biopsy

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AML outcomes

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Most pts relapse in median of 1-1.5 years and are incurable by chemo alone.

1/3 can be cured by BM or periph blood stem cell transplant (the tx of choice for relapsed AML)

Pts over 60 do poorly.

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Acute promyelocytic leukemia

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APL - t(15;17) AKA M3.

Nucleus has characteristic bilobed, folded appearance.

Dx made by histo/flow cytometry. PCR to ensure PML/RAR alpha is there.

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AML flow cytometry - what it means

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If lots of blasts and not many B/T cell markers, it is AML.

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Tx of AML (aside from APL)

first concerns

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First concerns
Treat infections, check cardiac func, leukostasis (if WBC>100K), hyperuricemia (lots of uric acid in blood), tumor lysis, DIC

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Tx of AML (aside from APL)

Chemotherapy

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Induction - Goal is remission. Myeloablative doses of chemo. This is dangerous time because pts are neutropenic at this point (can't transfuse WBCs)

Consolidation - After remission, 1-3 more courses of myeloablative chemo.

Autologous transplant - Patient's own hematopoietic stem cells are collected and frozen. Pt then given lots of chemo and stem cells are re-introduced to rescue the BM. This allows for higher doses of chemo.(for high risk patients)

Allogeneic transplant - Pt given high doses of chemo and stem cells from a donor. Additional benefit of graft vs leukemia where donors stem cells respond against the leukemia.

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APL presentation

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DIC is common

APL granules contain tumor cell procoagulants. (tissue factor activates factor VII and cancer activates X

But these patients usually just keep bleeding bc they dont have platelets. (lots of consumption of factors and platelets!)

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APL pathophys

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Normal levels of RARa heterodimerizes with RXRa to displace N-CoR and allow for transcription and differentiation.

But in this case, PML/RARa has less sensitivity to retinoic acid displacement of N-CoR. So there is no differentiation.

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APL treatment

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ATRA - overcomes reduced sensitivity to retinoic acid and displaces NCOR and allows txpn and differentiation to occur. This results in maturation of promyelocytes.

Usually in combo with chemo.

Very treatable - 85% 3 year survival.

Arsenic - induces apoptosis via PML/RAR-alpha protein interaction.

Most treatment failures duie from hemorrhage from initial DIC

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Promyelocyte characteristics

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Primary granules that contain pro-coagulants.

Front 36

ATRA SE

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Retinoic acid syndrome and hyperleukocytosis (huge increase in WBC numbers)

Front 37

Retinoic acid syndrome

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25% of APL pts
Usually in 1st 3 weeks of tx

Symptoms - Fever, edema, pulmonary infiltrates, resp distress.

Etiology is unclear. Must stop ATRA immediately.