Hematology 425 Myeloproliferative Disorders

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Hematology 425 Myeloproliferative Disorders

• Russ Morrison
• December 1, 2006

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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

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Myeloproliferative Disorders

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

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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

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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

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MPD - CML

• 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

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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

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MPD PV

• 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
  and
• 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

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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

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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
  BM

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MPD - ET

• Patients with ET experience relatively long
  survival rates provided they remain free from
  serious thromboembolic or hemorrhagic
  complications
• 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

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MPD - ET

• Other symptoms include headache, dizziness,
  visual disturbances and dyaesthesias (decreased
  sensations)
• 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

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MPD - ET

• 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
  common
• Adverse prognosis occurs in patients whose cells
  manifest chromosomal abnormalities

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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

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MPD - AMM

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

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MPD - AMM

• 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
  hypertension

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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

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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
  cell

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Hodgkin Lymphoma

• Historically survival rates have been extremely
  low
• 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

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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

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Malignant Lymphoma

• B-Cell Neoplasms include
• Small-Cell Lymphocytic Lymphoma and CLL
• Lymphoplasmacytoid Lymphoma or Waldenstrom
  Macroglobulinemia
• 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

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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

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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

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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

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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

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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

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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

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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

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MDS

• 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
  MDS

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MDS

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

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MDS

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

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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
  include
• Age
• Physical condition
• Patients preference
• Expense
• Availability of donors (transplants)
• Progression or stage of disease
• Experimental drugs/trials available

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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

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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

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Treatment of Leukocyte Neoplasia

• Unfortunately, for many patients with leukocyte
  neoplasms, remission is the realistic goal of
  therapy
• 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)

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Treatment of Leukocyte Neoplasia

• Treatment should be started immediately after
  diagnosis, but the future of a patients life
  wrapped in treatment decisions cannot be
  overemphasized
• 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

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Treatment of Leukocyte Neoplasia

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

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Chemotherapy

• Chemotherapy can be defined as the treatment of
  cancer with the use of compounds with antitumor
  properties
• 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

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Chemotherapy

• 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

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Chemotherapy

• 2 subgroups of phase nonspecific agents
• Cycle-specific, kill cells that are moving
  through the cell cycle (alkylating agents,
  cisplatin)
• 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

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Chemotherapy

• Chemotherapy agents are categorized into 5 main
  groups
• 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

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Chemotherapy

• 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

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Chemotherapy

• 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

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Chemotherapy

• 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

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Chemotherapy

• 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
  inhibited
• Table 38-1 depicts the chemotherapeutic agents,
  uses and toxic side effects

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Radiotherapy

• 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
  stopped

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Radiotherapy

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

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Biologic Response Modifiers

• These are substances produced naturally in the
  human body that are used to help treat cancer,
  BRMs
• 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

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BRMs

• 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

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BRMs

• 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

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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

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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
  isolation
• There are 3 types of donors
• Identical twin (syngeneic), most successful
• Allogeneic
• Autologous

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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)

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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

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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

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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

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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
  auto-transplantation
• Morbidity and mortality post-transplant is lower,
  hospital stays shorter for the auto pt
• Relapse rate is higher among auto recipients

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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,
  bleeding)
• Complications of GVHD
• Relapse (re-growth of malignant cells)
• Failure of donor cells to engraft