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Hematology 425 Myeloproliferative Disorders


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Title: Hematology 425 Myeloproliferative Disorders

Hematology 425 Myeloproliferative Disorders
  • Russ Morrison
  • December 1, 2006

Myeloproliferative Disorders
  • MPDs are clonal hematopoietic stem cell diseases
    that result in expansion and excessive production
    /overaccumulation of erythrocytes, granulocytes
    and platelets in some combination in the BM, PB
    and body tissues
  • They are considered together because they express
    common clinical features, laboratory changes and
    pathogenic similarities

Myeloproliferative Disorders
  • MPDs are classified according to predicted length
    of the disease as chronic, subacute or acute
  • The subacute group is termed myelodysplastic
  • The acute diseases are one of the variants in the
    acute myelogenous leukemia classification group

Myeloproliferative Disorders
  • Chronic MPDs include the chronic myelogenous
    leukemia, CML, polycythemia vera, PV, essential
    primary thrombocytopenia, ET, and agnostic
    myeloid metaplasia, AMM
  • MPD patients present in a clinically stable phase
    that may transform to an aggressive cellular
    growth phase such as acute leukemia
  • MPD may also manifest a depleted cellular phase
    such as bone marrow hypoplasia ORR exhibit
    clinical symptoms and morphology resembling a
    more aggressive expression of chronic MPD

Myeloproliferative Disorders
  • During the transition to acute leukemia, some
    patients may show progressive clinical symptoms
    and morphology similar to subacute MPD processes
  • MPDs may show familial inheritance where two or
    more members of a family have similar or
    different MPD syndromes
  • Childhood MPDs express as juvenile CML and
    pediatric myelodysplastic syndrome and are
    associated with monosomy or deletions of the long
    arm of C7

  • CML is a MPD arising as a clonal process in a
    pluripotential hematopoietic stem cell and
    manifesting with a chronic clinical phase which
    in 3-4 years terminates as an accelerated acute
    phase resembling acute leukemias
  • CML was discussed in Chapter 34 and is included
    here to show grouping with the MPDs

MPD Polycythemia Vera, PV
  • PV is a neoplastic clonal MPD that expresses with
    panmyelosis in the bone marrow and increases in
    RBCs, granulocytes and platelets in the PB
  • Splenomegaly is common
  • In PV, the clonal stem cells are extremely
    sensitive to EPO for cell growth
  • Splenomegaly and hepatomegaly as well as
    generalized vascular engorgement and circulatory
    disturbances often increase a patients risk for
    the complications of hemorrhage, tissue
    infarction or thrombosis

  • Clinical diagnosis of PV includes
  • an increased RBC mass
  • Arterial oxygen saturation of 92 or greater
  • Splenomegaly
  • Dx may also be made if one of the above is absent
  • Thrombocytosis 400 x 109/L
  • WBC 12 x 109/L without fever or infection or
    increases in LAP, serum vitamin B12 or unbound
    vitamin B12 binding capacity

MPD PV Therapy Prognosis
  • Treatments include 32P or alkylating agents
  • The chemotherapy treatments put the patient at
    risk for progression to acute leukemia, and are
    usually avoided
  • Symptoms may be reduced by blood letting
    (therapeutic phlebotomy)
  • Low dose aspirin is often prescribed to reduce
    the risk of thrombotic complications
  • There is no cure

MPD Essential Thrombocythemia
  • Essential thrombocythemia, ET, represents a
    clonal MPD involving increased megakaryopoiesis
    with thrombocytosis greater than 600 x 109/L and
    commonly above 1000 x109/L
  • The striking feature of the PB is increased
    platelets, it is also the main change seen in the

  • Patients with ET experience relatively long
    survival rates provided they remain free from
    serious thromboembolic or hemorrhagic
  • Clinical symptoms are those seen in
    vaso-occlusive events including burning
    sensations in the hands and feet
  • Other thrombotic symptoms include mottled red
    areas of the skin, transient ischemic attacks,
    seizures, and cerebral or myocardial infarction

  • Other symptoms include headache, dizziness,
    visual disturbances and dyaesthesias (decreased
  • Hemorrhagic complications include bleeding from
    oral and nasal mucous membrane or GI mucosa and
    apperiance of cutaneous ecchymoses
  • Treatment involves prevention or early
    intervention in hemorrhagic or vaso-occlusive
    complications which tend to appear as the
    platelet count rises

  • Chemotherapy is the same as in PV, but the risks
    are also the same, progression to acute leukemia,
    so avoided as last resort
  • Apheresis may be used to reduce platelet counts
  • Median survival rates of greater than 10 years is
  • Adverse prognosis occurs in patients whose cells
    manifest chromosomal abnormalities

MPD Agnogenic Myeloid Metaplasia - AMM
  • AMM expresses with ineffective hematopoiesis,
    marrow hypercellularity (especially increased
    megakaryocytes), bone marrow fibrosis,
    splenomegaly and hepatosplenomegaly
  • PB exhibits immature granulocytes and nRBCs,
    teardrop cells are common
  • Platelets may be normal, increased or decreased
    with abnormal morphology and micromega-karyocytes
  • Immune responses are altered in half of patients

  • AMM occurs in older patients and presents with
    symptoms of fatigue, weakness, SOB, palpitations,
    weight loss, and pain in the LUQ associated with
  • Average survival is 5 years
  • Mortality is associated with infection, severe
    hemorrhage, postsplenectomy complications and
    transformation to acute leukemia

  • AMM is also called myelofibrosis
  • Is typified by extramedullary hematopoiesis and
    accumulation of clonal stem cells in the liver,
    sspleen, adrenals, kidney, lymph node, bowel,
    breast, lungs, mediastinum, mesentery, skin,
    synovium, thymus and lower urinary tract as well
    as in body cavities
  • Treatment is to alleviate symptoms or modify
    clinical problems
  • Splenectomy is performed to end severe pain,
    reduce the need for transfusion or
    thrombocytopenia and to correct portal

Lymphoproliferative Disorders
  • Lymphoproliferative disorder refers to a large
    group of neoplastic lesions of the lymphoid
    system including
  • Hodgkin lymphoma
  • Non-Hodgkin lymphoma
  • Plasma cell dyscrasias
  • Chronic lymphocytic leukemias (CLLs)
  • Other lymphoid proliferations that behave in an
    aggressive fashion

Lymphoproliferative Disorders
  • The LPDs are broadly divided into Hodgkin and
    non-Hodgkin lymphomas
  • Hodgkin lymphoma is a malignant
    lymphoproliferative disorder associated with
    fevers, night sweats and cervical adenopathy
  • Diagnosis is characterized by the Reed-Sternberg

Hodgkin Lymphoma
  • Historically survival rates have been extremely
  • Combined chemotherapy and irradiation regimens
    now result in overall survival and cure rates of
    at least 80
  • Clinical course varies with age and state of
    disease as well as histologic subtype
  • Patients are at risk for developing secondary
    malignancies including solid tumors (breast,
    lung, bone and soft tissue) as well as acute
    leukemia, sometimes several years after a cure

Non-Hodgkin Lymphoma
  • Non-Hodgkin lymphomas include a varied group of
    disorders that differ in microscopic appearance,
    immunologic origin and biologic behavior
  • Subtypes of malignant lymphoma are are broadly
    divided into B-cell and T-cell neoplasms

Malignant Lymphoma
  • B-Cell Neoplasms include
  • Small-Cell Lymphocytic Lymphoma and CLL
  • Lymphoplasmacytoid Lymphoma or Waldenstrom
  • Mantle Cell Lymphoma
  • Follicle Center Lymphoma
  • Marginal Zone B-Cell Lymphoma
  • Multiple Myeloma/Plasmacytoma/Monoclonal
  • Gammopathy of Uncertain Significance
  • Diffuse Large B-Cell Lymphoma
  • Burkitt Lymphoma

Malignant Lymphoma
  • T-Cell Neoplasms include
  • Precursor T-Cell Lymphoblastic Leukemia/Lymphoma
  • Mycosis Fungoides/Sezary Syndrome
  • Peripheral T-Cell Lymphoma
  • Anaplastic Large-Cell Lymphoma
  • Other malignant lymphomas are Histiocytic
    Lymphoma, Composite Lymphoma and Malignant
    Lymphoma in the Immunocompromised Patient

Malignant Lymphoma
  • Individuals with AIDS are at risk for
    lymphoproliferative disorders, especially the
    high-grade malignant lymphomas
  • Transplant patients may also develop a wide array
    of post-transplant lymphoproliferative disorders
    as a complication of immunosuppression

Lymphoproliferative Disorders
  • The LPDs include a large group of benign and
    malignant lesions involving the lymphoid system
  • Malignant processes are frequently derived from a
    single clone of cells and demonstrate immunologic
    or molecular features of a clonal proliferation
  • Appropriate recognition and classification
    involves integration of clinical and morphologic
    findings along with immunophenotyping,
    cytogenetics and molecular diagnostics

Myelodysplastic Syndromes
  • MDS are a group of acquired clonal hematologic
    disorders characterized by progressive cytopenias
    in the PB
  • They reflect defects in erythroid, myeloid,
    and/or megakarocytic maturation
  • Occur most frequently in people over age 50
  • Seem to be increasing, but it could just be
    related to the changing demographic and increase
    in the population of the over 60 age group

MDS - Etiology
  • 3 types of MDS
  • Primary
  • Therapy-related
  • Hereditary
  • All of the MDS are the result of proliferation of
    abnormal stem cells
  • The theory is that the abnormal stem cell is the
    result of cumulative effects of environmental
    exposure in susceptible individuals
  • There seems to be an association with smoking

MDS - Etiology
  • The abnormal stem cell may result from chemical
    exposure, radiation or viral infection
  • MDS have a multitude of expressionns, but 2
    morphologic findings are common to all types
  • Presence of progressive cytopenias despite
    cellular BM
  • Dyspoiesis in one or more cell lines

MDS - Etiology
  • TR-MDS occurs in patients who have been treated
    with chemotherapy and/or radiotherapy
  • Onset of TR-MDS is usually 2-5 years after the
    therapy was initiated
  • TR-MDS is often more aggressive and may quickly
    evolve into AML

  • Dyserythropoiesis, dysmyelopoiesis and/or
    dysmegakaryopoiesis may occur in MDS
  • Cells produced not only have abnormal appearance
    but also abnormal function
  • FAB Classification of MDS according to
    morphologic criteria is listed in table 37-1
  • Cell surface markers and gene rearrangement
    studies available through molecular diagnostics
    are becoming an integral part of the diagnosis of

  • Prognosis depends on several factors
  • Classification
  • BM blasts
  • Cytopenias
  • Karyotypic abnormalities
  • Treatment depends on prognosis and often is
    limited to supportive therapy

  • Other treatments that have been attempted include
    chemotherapy and biologic response modifiers
  • The only cure, currently, for MDS is bone marrow
  • Research is currently underway to refine and
    trial an apoptosis-controlling drug

Treatment of Leukocyte Neoplasia
  • Treatments of blood cancers are diverse and
    constantly changing
  • They are the subject of intense research and
    clinical trials
  • Criteria used to decide a course of treatment
  • Age
  • Physical condition
  • Patients preference
  • Expense
  • Availability of donors (transplants)
  • Progression or stage of disease
  • Experimental drugs/trials available

Treatment of Leukocyte Neoplasia
  • Optimization of treatment requires
  • Accurate diagnosis (type and subtype)
  • Respect for the patient as an individual
    (feelings, emotions, finances, family support)
  • Consideration of all of the alternatives in
    discussion with the patient and family
  • If a cure is attainable, it is usually the goal
    of therapy

Treatment of Leukocyte Neoplasia
  • Cure is a realistic goal in
  • Early stage Hodgkin and non-Hodgkin lymphoma
  • Children with ALL
  • BM transplant is given consideration in CML, AML,
    ALL and other malignancies where BM
    transplantation has shown success
  • CML has had higher success with treatment since
    the introduction of Gleevec in 2001

Treatment of Leukocyte Neoplasia
  • Unfortunately, for many patients with leukocyte
    neoplasms, remission is the realistic goal of
  • Treatment is rigorous and supportive care will
    make an essential difference in survival and
    quality of life during treatment
  • When side effects of therapy cause more morbidity
    than the neoplasm, it may be more humane to omit
    therapy in favor of supportive care
    (transfusions, pain killers, fulfilling end of
    life wishes)

Treatment of Leukocyte Neoplasia
  • Treatment should be started immediately after
    diagnosis, but the future of a patients life
    wrapped in treatment decisions cannot be
  • Quality of life must always be considered and the
    treatment should never be worse than the disease
  • If treatment is not likely to offer any short- or
    long-term benefits, the best course may be no
    treatment at all

Treatment of Leukocyte Neoplasia
  • There are 4 major methods of treating leukocyte
  • Chemotherapy
  • Radiotherapy
  • Biologic response modifiers
  • Bone marrow/peripheral blood stem cell

  • Chemotherapy can be defined as the treatment of
    cancer with the use of compounds with antitumor
  • Drugs are administered orally of parenterally
  • Methods of action vary considerably, but can be
    classified in two ways
  • By their effect on the cell cycle
  • By their biochemical mechanism of action

  • Phase specific drugs affect specific phases of
    the cell cycle
  • Phase nonspecific drugs act without regard to the
    cell cycle and affect any phase of the cell cycle
  • Phase nonspecific agents usually have a linear
    dose-response curve (the higher the dose, the
    more cells are killed

  • 2 subgroups of phase nonspecific agents
  • Cycle-specific, kill cells that are moving
    through the cell cycle (alkylating agents,
  • Cycle-nonspecific agents, wich kill non-dividing
    cells or cells in the resting state (steroids,
    antitumor antibiotics)
  • Chemotherapeutics affect normal and neoplastic
    cells and are harder on rapidly dividing cells of
    the mucosa of the GI tract and bone marrow which
    is a limiting factor in dosage

  • Chemotherapy agents are categorized into 5 main
  • Alkylating agents
  • Ionize within cells forming highly reactive free
    radicals that damage DNA
  • Act on any phase of the cell cycle
  • Include nitrogen mustard, cyclophosphamide,
    chlorambucil, busulfan, melphalan

  • Plant alkaloids
  • Plant alkaloids (stathmokinetic agents), affect
    microtubules and interrupt the process of mitotic
    spindle formation during the metaphase of mitosis
  • Examples include vincristine and vinblastine

  • Antitumor Antibiotics
  • Compounds derived from living microorganisms
  • Inhibit RNA or DNA synthesis and interfere with
    the G2 phase of the cell cycle
  • Include daunorubicin and doxorubicin

  • Antimetabolites
  • Interfere with the normal functions of various
    essential metabolites
  • Examples include methotrexate, folate
    antagonists, and the purine analogues such as
    6-mercaptopurine and 6-thioguanine

  • Glucocorticoids
  • Synthetic or natural steroids include compounds
    such as hydrocortisone, prednisone, dexamethasone
    and prednisolone
  • Have a lympholytic effect and affect
    nonproliferating cells as well as those in cycle
  • Protein synthesis and mitosis may also be
  • Table 38-1 depicts the chemotherapeutic agents,
    uses and toxic side effects

  • Radiation kills cells by producing unstable ions
    that damage DNA and cause instant or delayed
    death of the cell
  • Used in treatment of Hodgkin and non-Hodgkin
    lymphoma soon after discovery of X-rays
  • The hematopoietic system, GI tract and skin are
    most often affected during radiotherapy
  • Toxic effects are reversible when radiation is

  • Radiation is used most commonly in the treatment
    of localized malignancies
  • Chemotherapy is the treatment of choice for
    diffuse malignancies

Biologic Response Modifiers
  • These are substances produced naturally in the
    human body that are used to help treat cancer,
  • CSF is used to support chemotherapy patients by
    stimulating rapid production and maturation of
    WBC lines
  • CSFs are also used to increase the effectiveness
    of chemotherapy

  • Another important BRM is interferon-a
  • Interferon-a has been used to induce remissions
    in hairy cell leukemia, B-cell leukemia and
    lymphoma, and CML
  • Interleukin-2 is a cytokine that activates
    cytotoxic T-cells and is effective in treating
    thymoma and renal cell carcinoma

  • Should be the most desirable of cancer treatments
    as they are selective without impacting normal
    cell lines
  • They should minimize side efffects as they are
    derived from human and animal sources
  • So far, BRMs have not been toxic enough to kill
    the tumor off and the tumor later returns
  • Research continues with much promise for BRMs

Bone Marrow Transplantation
  • Had a bad rap because of low survival rates
  • Now a curative treatment for selected disorders
  • Unrelated donors are easier to find due to the
    National Bone Marrow Donor Program
  • The more closely matched the donors and
    recipients cells are, the less likely the
    recipient will experience GVHD

Bone Marrow Transplantation
  • An expensive and rigorous treatment alternative
  • Donor has to be found
  • Preconditioning lowers the patients immune
    status to dangerous levels requiring protective
  • There are 3 types of donors
  • Identical twin (syngeneic), most successful
  • Allogeneic
  • Autologous

Allogeneic BMT
  • Match as many of the human leukocyte antigens
    (HLAs) as possible
  • Within a given family, there can be only 4 HLA
    haplotypes (2 from mom, 2 from dad)
  • Every patient has a 1 in 4 chance of having an
    HLA-identical sibling
  • Major complication is the immunologic reaction of
    donor T cells against the tissues of the
    recipient (GVHD)

Allogeneic BMT
  • GVHD is characterized by skin rash, liver
    dysfunction and diarrhea
  • Skin lesions, joint contractures, chronic
    hepatitis, malabsorption and COPD are features of
    chronic GVHD
  • Clinically significant GVHD carries with it a 25X
    higher risk of fatality for the transplant patient

Allogeneic BMT
  • T-cell depletion of the donor bone marrow is the
    most effective means of preventing acute and
    chronic GVHD
  • Preventing GVHD increases the risk of leukemic
    relapse and infections
  • Evidence indicates that allogeneic grafts lower
    the risk of leukemic relapse
  • The antileukemia effect is most pronounced in the
    presence of chronic GVHD

Autologous Transplantation
  • In an autologous BMT, marrow is harvested from
    the patient and, after conditioning, is
    transplanted back into them
  • Harvested remission marrow is purged in vitro
    through use of anti-leukemic monoclonal
    antibodies or cytotoxic drugs
  • The patient is conditioned with cyclophosphamide
    and total body irradiation to eradicate remaining
    malignant cells
  • The purged marrow is reinfused

Autologous Transplantation
  • A requirement for success in the auto-transplant
    is the presence of normal multipotent stem cells
    and purging of the malignant cells to a level
    insufficient to cause recurrence from the
    reinfused marrow
  • Comparing auto- to allo-transplantation
  • Almost every patient is eligible for
  • Morbidity and mortality post-transplant is lower,
    hospital stays shorter for the auto pt
  • Relapse rate is higher among auto recipients

Autologous Transplantation
  • Techniques have recently been developed to
    collect peripheral blood stem cells for
    transplantation, response rates are comparable to
    standard BMT
  • Death from transplantation is caused by
  • Complications of conditioning (infections,
  • Complications of GVHD
  • Relapse (re-growth of malignant cells)
  • Failure of donor cells to engraft
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