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    CLL

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    Bharath Sunkam

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    © All Rights Reserved
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    CLL

    Uploaded by

    Bharath Sunkam
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    CLL

    Uploaded by

    Bharath Sunkam

    Copyright:

    © All Rights Reserved
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    CHRONIC LYMPHOCYTIC

    LEUKEMIA
    MBL / SLL / CLL

    Small lymphocytic lymphoma

    Monoclonal B-cell lymphocytosis

    Chronic lymphocytic leukemia


    Monoclonal B-cell Lymphocytosis (MBL)
    Presence of malignant B cells (<5000 cells) in the
    blood without nodal, spleen, or liver
    involvement and absent cytopenia.

    MBL CLL
    Chronic lymphocytic leukemia (CLL) is a
    monoclonal proliferation of
    mature B lymphocytes defined by an
    absolute number of malignant
    cells in the blood (>5000 cells).

    Rare in the Asian population


    HARRISON 19TH
    CLL

    • The diagnosis of typical B-cell CLL is


    made when an increased number of
    circulating lymphocytes ( >4000 cells
    and usually >10,000 cells) is found that
    are monoclonal B cells expressing the
    CD5 antigen.
    Indeed, CLL is one of
    the only types of
    leukemia not linked to
    radiation exposure.
    • CLL is one of the most familial-associated
    malignancies, and the first-degree relative of a
    CLL patient has an 8.5-fold elevated risk of
    developing CLL than the general population.

    • MBL is also more common in families with two


    first-degree relatives having CLL, further
    supporting a genetic predisposition of this
    disease.
    B-Cell Receptor Signaling

    • Spleen tyrosine kinase

    • Phosphoinositide-3-kinase (PI3K)

    • Bruton’s tyrosine kinase (BTK)


    Variable regions
    of immuno
    Normal B-cell globulin Heavy Somatic
    maturation chain hypermutation
    IgHv
    IGVH

    ≥2% mutated <2% mutated


    (60%) (40%)

    More rapid
    More indolent progression of
    disease course disease and
    short survival
    IGHV unmutated
    CLL cells

    Zap-70
    protein

    CD38
    del 13

    del Trisomy
    11,17 12
    MDS - RS
    SIDEROBLAST
    MDS - T

    SF3B1
    SMUDGE CELL
    Adult T Cell
    HTLV 1 TSP
    Leukemia

    HTLV-1 encodes a protein called Tax that is


    a potent activator of NF-κB, which, enhances
    lymphocyte growth and survival
    Mycosis Sezary
    CTCL
    fungoides syndrome
    CD 19 CD 20

    CD 22
    CD 5
    CD 23

    Surface Ig
    positive
    CD 23 -VE
    INFECTIONS

    Infections are a leading cause of death

    Immune dysfunction
    Disease & Therapy

    Typical and atypical infections

    Vaccine responses
    AUTOIMMUNE COMPLICATIONS

    • Most commonly - Autoimmune cytopenias

    • MC- AIHA > ITP

    • These two syndromes may occur in isolation,


    sequentially in the same patient, or present in
    combination as Evan’s syndrome.
    Secondary
    Skin
    malignancies
    DLBL
    Prolymphocytic
    (Richter
    transformation syndrome )
    Risk factors for development

    • Bulky lymphadenopathy
    • NOTCH1 mutations
    • del(17)
    • Specific stereotyped IGVH usage
    • Lymphomas arising in the setting of CLL can
    either be

     Clonally related
    or
     Unrelated to the initial CLL

    • With prognosis significantly better for clonally


    unrelated lymphomas (~5 years).
    Clinical signs - Richter’s transformation

    • Rapid progression in adenopathy - specific


    area
    • Constitutional symptoms
    • Suspected cases - first step is PET/CT
    • Standardized uptake values (SUV) ≥10

    • Therapy - chemoimmunotherapy
    Prognostic
    marker

    Cytogenetics

    Molecular
    aberrations
    Complete remission Definition
    ALC <4000

    Lymph nodes None >1.5 cm

    Spleen/liver size Not palpable


    Normo cellular
    Bone marrow <30% Lymphocytes
    No B lymphoid nodules

    Hb >11 g/dL
    Peripheral blood counts PLT >100,000
    ANC >1500
    Dr Kanti Roop Rai
    Physical Laboratory
    examination studies

    Disease bulk Do not require


    Marrow Imaging or BM
    failure analysis
    • Imaging with CT scan is usually not necessary
    unless there are symptoms and concern for
    intra-abdominal nodes out of proportion to
    peripheral nodes.

    • Bone marrow biopsy is not undertaken until


    therapy is initiated except in cases of
    unexplained cytopenias.
    Initial staging systems could reliably
    predict survival in CLL
    Treatment

    Chemotherapy
    Chemo
    immunotherapy

    Supportive
    care
    Anti-CD20 monoclonal antibodies

    Rituximab

    Ofatumumab Obinutuzumab
    For patients who are young (≤65 years),
    the gold standard for therapy is a combination
    of the nucleoside analogue fludarabine, the
    alkylator cyclophosphamide, and the anti-CD20
    monoclonal antibody Rituximab

    (FC vs FCR Regimen)


    Older patients Chlorambucil
    Obinutuzumab
    or
    or
    Multiple Bendamustine
    comorbidities Rituximab
    B-Cell Receptor Signaling

    • Phosphoinositide-3-kinase (PI3K) - Idelalisib

    • Bruton’s tyrosine kinase (BTK) - Ibrutinib


    Antiapoptotic Therapies

    • Selective BCL2 inhibitor


    • Venetoclax - orally bioavailable

    • Approved for patients with relapsed or refractory


    CLL who have the del(17).

    • Induce very deep responses including CRs with


    minimal residual disease negativity in a subset of
    patients.
    Stem cell transplantation is currently
    considered the only standard curative
    approach to CLL.

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