CLL, HCL, CML

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CLL, HCL, CML

• Mirzania.MD
• pathophysiology

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Epidemiology and clinical manifestations of
chronic lymphocytic leukemia
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• Chronic lymphocytic leukemia (CLL) is one of the
  chronic lymphoproliferative disorders (lymphoid
  neoplasms).
• It is characterized by a progressive
  accumulation of functionally incompetent
  lymphocytes, which are monoclonal in origin.

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EPIDEMIOLOGY

•  CLL is the most common leukemia in Western
  countries
• The disorder is more common in men with a male to
  female ratio of approximately 1.71.
• CLL is considered to be mainly a disease of the
  elderly, with a median age at diagnosis of 70
  years.
• Genetic rather than environmental factors are the
  most likely explanation for these differences.
• higher incidence among Caucasians as compared
  with African Americans or Asian Pacific Islanders

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CLINICAL PRESENTATION

• Symptoms 
• painless swelling of lymph nodes, often in the
  cervical area, which spontaneously wax and wane,
  but do not altogether disappear.
• Approximately 25 percent of patients feel
  entirely well with no symptoms when a routine
  blood count reveals an absolute lymphocytosis,
  leading to a diagnosis of CLL.
• Five to 10 percent of patients present with the
  typical "B" symptoms .

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Symptoms 

• an acquired immunodeficiency disorder,
  manifested by infections,
• autoimmune complications such as hemolytic
  anemia, thrombocytopenia or pure red cell
  aplasia, or exaggerated reactions to insect
  stings or bites (especially mosquito).

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Signs

• Lymphadenopathy  The most common abnormal
  finding present in 50 to 90 percent of patients
  among various series.
• enlargement may be generalized or localized
• The most commonly affected sites are cervical,
  supraclavicular, and axillary.
• enlarged nodes in CLL are firm, rounded,
  discrete, nontender, and freely mobile upon
  palpation.

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Signs

• Splenomegaly  The spleen is the second most
  frequently enlarged lymphoid organ, being
  palpably enlarged in 25 to 55 percent of cases.
• usually painless, and nontender to palpation,
  with a sharp edge and a smooth firm surface.
• Hepatomegaly  Enlargement of the liver may be
  noted at the time of initial diagnosis in 15 to
  25 percent of cases.

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Signs

• Skin  Infiltration in the skin (leukemia cutis)
  is the most commonly involved non-lymphoid organ.
  These lesions most commonly involve the face and
  can manifest as macules, papules, plaques,
  nodules, ulcers, or blisters
• Nonspecific secondary cutaneous lesions may be
  due to infection, bleeding, vasculitis, or
  paraneoplastic pemphigus.
• Membranoproliferative glomerulonephritis  Membran
  oproliferative glomerulonephritis (MPGN) has
  occasionally been described in CLL, and appears
  to be a paraneoplastic phenomenon mediated by
  deposition and possibly processing of
  cryoprecipitating or noncryoprecipitating
  M-components .

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Signs

• Other organ involvement  Virtually any lymphoid
  tissue may be enlarged at diagnosis, including
• Waldeyer's ring in the pharynx.
• In contrast to other lymphomas, gastrointestinal
  mucosal involvement is rarely seen in CLL.
• Similarly, meningeal leukemia is unusual at the
  time of initial presentation.

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LABORATORY ABNORMALITIES

• Lymphocytosis   the absolute blood lymphocyte
  threshold for diagnosing CLL has been placed at
  gt5000/microL 5 x 10(9)/L B lymphocytes , a
  significant proportion of patients present with
  counts as high as 100,000/microL 100 x 10(9)/L.
  
• Cytopenias  Neutropenia, anemia and
  thrombocytopenia may be observed at the time of
  initial diagnosis, and are usually not severe.
  These can be related to autoimmune hemolytic
  anemia, pure red cell aplasia, autoimmune
  thrombocytopenia, or agranulocytosis.

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LABORATORY ABNORMALITIES

• Immunoglobulin abnormalities  Hypogammaglobulinem
  ia is present in approximately 8 percent of
  patients at the time of initial diagnosis and may
  develop in up to two-thirds of patients later in
  the course of the disease. Usually all three
  immunoglobulin classes (IgG, IgA, and IgM) are
  decreased.
• Polyclonal increases in gamma globulins can be
  seen in up to 15 percent of patients, while a
  monoclonal protein, usually of the same class as
  the surface membrane immunoglobulin, is present
  in up to 5 percent of patients.

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LABORATORY ABNORMALITIES

• Other abnormal findings 
• elevated levels of serum lactate dehydrogenase
  (LDH) and beta-2 microglobulin were found in 60
  percent of patients in one series.
• Elevations of uric acid, hepatic enzymes (ALT or
  AST) and, rarely, calcium may also be observed.

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immunophenotype

• Expression of one or more B-cell associated
  antigens as demonstrated by CD19, CD20, CD21,
  CD23, and CD24.
• Expression of CD5, a T-cell associated antigen

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Staging and prognosis of chronic lymphocytic
leukemia

• NATURAL HISTORY 
•  prolonged (ie, 10 to 20 years) clinical
  course(1/3).
• Some patients die rapidly, within two to three
  years from diagnosis.
• Other patients live for 5 to 10 years with an
  initial course that is relatively benign followed
  by a terminal phase lasting one to two years.
  During this terminal phase there is considerable
  morbidity, both from the disease itself and from
  complications of therapy.
• during the terminal phase the performance status
  is poor, with recurring need for hospitalization.
  The most frequent causes of death are severe
  systemic infection (especially pneumonia and
  septicemia), bleeding, and inanition with
  cachexia.

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CLINICAL STAGING AND PROGNOSIS

•   the natural history of CLL is extremely
  variable, with survival times from initial
  diagnosis that range from 2 to 20 years, and a
  median survival of approximately 10 years.

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Rai stage

• Stage 0 150 months
• Stage I 101 months
• Stage II 71 months
• Stages III and IV 19 months

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HISTOLOGIC TRANSFORMATION 

• Prolymphocytic leukemia 10 percent
• Aggressive or highly aggressive lymphoma
  (Richter's transformation) 3 percent
• Hodgkin lymphoma 0.5 percent
• Multiple myeloma 0.1 percent

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Prolymphocytoid transformation

•  In approximately 10 percent of patients with
  CLL, the terminal event is a morphological
  transformation of blood lymphocytes
• from the typical small, mature-appearing cell
• to somewhat larger cells with distinct nucleoli
  and a less dense nuclear chromatin. This event,
  called prolymphocytoid transformation, occurs
  slowly over years and is associated with
  refractoriness to the usual chemotherapeutic
  agents.

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Richter's syndrome or Richter's transformation

•  In 1 to 10 percent of patients with CLL,
  transformation to a highly aggressive non-Hodgkin
  lymphoma supervenes.
• This transformation is heralded by sudden
  clinical deterioration, characterized by
  increasing lymphadenopathy, splenomegaly,
  worsening "B" symptoms, a rapidly progressive
  downhill clinical course, and a median survival
  of 5 to 8 months.

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transformation

• Acute leukemic transformation  Acute leukemia is
  a rare terminal event in CLL and, when it does
  occur, is usually one of the myeloid variants
  (ie, acute myeloid leukemia, AML).
• Prior therapy with alkylating agents has not been
  clearly implicated in causation of terminal
  leukemia.
• Second malignancies  Patients with CLL are at a
  higher risk than the general population to
  develop another cancer, usually of the lung,
  skin, and bone

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INDICATIONS FOR TREATMENT 

• With the possible exception of allogeneic
  hematopoietic cell transplantation (HCT), CLL
  cannot be cured by current treatment options.
• Prospective, randomized trials evaluating
  immediate versus delayed treatment strategies
  have found no improvement in long-term survival
  with early treatment.

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Therapy is indicated for patients with the
following disease-related complications

• Weakness, night sweats, weight loss, painful
  lymphadenopathy, or fever.
• Symptomatic anemia and/or thrombocytopenia.
• Autoimmune hemolytic anemia and/or
  thrombocytopenia poorly responsive to
  corticosteroid therapy.
• Progressive disease, as demonstrated by
  increasing lymphocytosis with a lymphocyte
  doubling time less than six months, and/or
• rapidly enlarging lymph nodes, spleen, and liver.
• Repeated episodes of infection.
  Hypogammaglobulinemia without repeated episodes
  of infection is not a clear indication for
  therapy.

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Clinical features and diagnosis of hairy cell
leukemia

• named HCL in the 1960s because of the prominent
  irregular cytoplasmic projections of the
  malignant cells.
• The clinical features and diagnosis of HCL, which
  is now considered one of the indolent non-Hodgkin
  lymphomas.

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INCIDENCE AND PATHOGENESIS 

• Hairy cell leukemia is an uncommon malignancy,
  representing about 2 percent of all leukemias.
• The median age at onset is 52
• there is a strong male predominance of about
  four to one.
• The incidence is about three times higher in
  Caucasians than in Blacks

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• The pathogenesis of HCL is unknown, although
• exposure to ionizing radiation,
• Epstein-Barr virus,
• organic chemicals,
• woodworking, and
• farming

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• The cell expresses pan B cell surface antigens
  (CD19, CD20, and CD22) and an early plasma cell
  marker (PCA-1). It does not express CD21, a
  marker for the immature B cell.
• The cell also expresses surface antigens that are
  not common on B cells, such as CD11c (monocytes
  and neutrophils), CD25 (activated T cells), and
  CD103 (intraepithelial T cells).
• Clonal karyotypic abnormalities are present in
  approximately two-thirds of patients.
  Abnormalities of chromosome 5 are present in
  approximately 40 percent

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CLINICAL PRESENTATION

• Approximately one-quarter present with abdominal
  fullness or discomfort due to splenomegaly, which
  may be massive. Spontaneous splenic rupture may
  occur, which constitutes a medical emergency.
• Another one-quarter present with systemic
  complaints such as fatigue, weakness, and weight
  loss. Patients do not usually complain of fever
  or night sweats.

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CLINICAL PRESENTATION

• Another one-quarter present either with bruising
  and bleeding secondary to severe
  thrombocytopenia, or with recurrent infections,
  which may be life-threatening, secondary to
  granulocytopenia and monocytopenia.
• The remaining one-quarter are generally
  asymptomatic and come to the clinician's
  attention because of an incidental finding of
  splenomegaly or cytopenias during evaluation for
  an unrelated cause.
• Occasional patients have vasculitis, usually
  polyarteritis nodosa or cutaneous
  leukocytoclastic vasculitis, or other autoimmune
  manifestations

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Physical examination

•  palpable splenomegaly in 80 to 90 percent of
  cases, with the splenic edge extending more than
  8 cm below the left costal margin in 25 percent.
• Hepatomegaly and lymphadenopathy are not major
  features of HCL, being present in about 20 and 10
  percent of patients, respectively.
• Rare physical findings include soft tissue
  infiltration, vasculitic skin rash, ascites, and
  pleural effusion.

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Laboratory findings

•  Sixty to 80 percent of patients with HCL present
  with pancytopenia, with hematocrits in the range
  of 20 to 35 percent, a total white blood cell
  count usually below 4000/microL, and platelet
  counts in the range of 20,000 to 100,000/microL.
• Abnormal liver function tests 20 percent
• Hypergammaglobulinemia 20 percent
• Leukocytosis (total WBC gt10,000/microL) 10 to
  20 percent

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DIAGNOSIS

• The abnormal cell in HCL about 90 percent of
  patients.
• Bone marrow examination  . Because of fibrosis,
  the BM is often inaspirable, resulting in a "dry
  tap.
• Reticulin  Staining of the BM trephine biopsy
  for reticulin almost always shows a moderate to
  marked increase in reticulin fibers.
• Cytochemical findings  Historically,
  demonstration of tartrate-resistant acid
  phosphatase (TRAP) activity on peripheral blood
  films, marrow aspirate smears, or touch
  preparations of BM was routinely used to confirm
  the diagnosis of HCL. TRAP-positive cells are
  found in almost all cases of HCL at diagnosis

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• Hairy cells strongly express pan-B cell antigens
  including CD19, CD20, CD22, and CD25, and
• usually lack expression of CD5, CD10, CD21, and
  CD23.
• Hairy cells characteristically express CD11c,
  CD103, CD123, cyclin D1, and annexin A1.

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INDICATIONS FOR TREATMENT

•  Many patients with HCL are asymptomatic and can
  be observed for months or years after the
  diagnosis is established before requiring
  treatment.
• Significant cytopenias typical peripheral blood
  counts that warrant treatment include an absolute
  neutrophil count lt1000/microL with repeated
  infections, symptomatic anemia with a hemoglobin
  concentration lt11.0 g/dL, or bleeding due to a
  platelet count lt100,000/microL
• Symptomatic splenomegaly (common) or symptomatic
  adenopathy (uncommon)
• Constitutional symptoms (eg, fever, night sweats,
  fatigue, weight loss)

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chronic myeloid leukemiaCML
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chronic myeloid leukemiaCML

• A myeloproliferative neoplasm characterized by
  the dysregulated production and uncontrolled
  proliferation of mature and maturing granulocytes
  with fairly normal differentiation.

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INTRODUCTION

• CML is associated with the fusion of two genes
  BCR (on chromosome 22) and ABL1 (on chromosome 9)
  resulting in the BCR-ABL1 fusion gene.
• This abnormal fusion typically results from a
  reciprocal translocation between chromosomes 9
  and 22, t(922)(q34q11), that gives rise to an
  abnormal chromosome 22 called the Philadelphia
  (Ph) chromosome.
• It is this derivative chromosome 22 which
  harbors the BCR-ABL1 fusion gene.

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INTRODUCTION

• The BCR-ABL1 fusion gene results the BCR-ABL1
  fusion protein.
• This protein product includes an enzymatic domain
  from the normal ABL1 with tyrosine kinase
  catalytic activity, but relative to ABL1, whose
  kinase activity is tightly regulated 1,
• the kinase activity of BCR-ABL1 is elevated and
  constitutive 2 due to fusion with a portion of
  BCR.
• It is this deregulated tyrosine kinase that is
  implicated in the pathogenesis of CML.

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INTRODUCTION

• The clinical hallmark of CML is the uncontrolled
  production of mature and maturing granulocytes,
  predominantly neutrophils, but also basophils and
  eosinophils.
• In the absence of treatment, CML has a triphasic
  or biphasic clinical course as it progresses from
  a chronic phase to an accelerated phase and on to
  a terminal blast crisis.
• Sometimes it goes from chronic phase directly to
  blast crisis, particularly when the blast phase
  is lymphoid.

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EPIDEMIOLOGY 

• CML accounts for approximately 15 to 20 percent
  of leukemias in adults.
• It has an annual incidence of 1 to 2 cases per
  100,000, with a slight male predominance.
• The median age at presentation is approximately
  50 years for patients enrolled on clinical
  studies.
• Exposure to ionizing radiation is the only known
  risk factor.
• There is no known familial predisposition.

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CLINICAL MANIFESTATIONS 

• CML has a triphasic or biphasic clinical course
• a chronic phase, which is present at the time of
  diagnosis in approximately 85 percent of
  patients
• an accelerated phase, in which neutrophil
  differentiation becomes progressively impaired
  and leukocyte counts are more difficult to
  control with treatment and
• blast crisis, a condition resembling acute
  leukemia in which myeloid or lymphoid blasts
  proliferate in an uncontrolled manner.

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CLINICAL MANIFESTATIONS

• Twenty to 50 percent of patients are
  asymptomatic, with the disease first being
  suspected from routine blood tests.
• Among symptomatic patients,
• fatigue (34 percent),
• malaise (3 percent),
• weight loss (20 percent),
• excessive sweating (15 percent),
• abdominal fullness (15 percent), and
• bleeding episodes due to platelet dysfunction
  (21 percent) are common.

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CLINICAL MANIFESTATIONS

• Abdominal pain and left upper quadrant pain
  (sometimes referred to the left shoulder) and
• early satiety, due to the enlarged spleen with or
  without
• splenic infarction.
• Tenderness over the lower sternum, due to an
  expanding bone marrow, is sometimes seen.
• Acute gouty arthritis may also present at this
  time, due to overproduction of uric acid.

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CLINICAL MANIFESTATIONS

• splenomegaly (present in 48 and 76 percent in
  two series),
• anemia (45 and 62 percent),
• white blood cell count above 100,000/microL (52
  and 72 percent), and
• platelet count above 600,000 to 700,000/microL
  (15 and 34 percent).
• Involvement of extramedullary tissues such as the
  lymph nodes, skin, and soft tissues is generally
  limited to patients with blast crisis.

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Peripheral blood

•  The peripheral smear typically demonstrates a
  leukocytosis with a median white count of
  approximately 100,000/microL (range 12 to
  1000/microL).
• The white blood cell differential typically shows
  virtually all cells of the neutrophilic series,
  from myeloblasts to mature neutrophils with peaks
  in the percent myelocytes and segmented
  neutrophils

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Peripheral blood

• Blasts typically account for less than 2
  percent.
• The presence of a greater percent of myelocytes
  than the more mature metamyelocytes ("leukemic
  hiatus" or "myelocyte bulge") is one of the
  classic findings in CML.
• The granulocytes of chronic phase are
  morphologically normal with no evidence of
  dysplasia, but dysplasia can develop in more
  advanced disease, and particularly in accelerated
  phase.

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leukocyte alkaline phosphatase (LAP, )

• The neutrophils in CML are cytochemically
  abnormal. The cytochemical reaction called
  leukocyte (or neutrophil) alkaline phosphatase
  (LAP, or NAP) when scored is low.
• The low LAP score is useful in excluding a
  reactive leukocytosis or "leukemoid reaction,"
  typically due to infection, in which the score is
  typically elevated or normal.
• Low LAP activity was also classically used to
  exclude polycythemia vera (PV) in the
  differential diagnosis of CML, in which LAP
  activity is also often increased.

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Peripheral blood

• The platelet count can be normal or elevated.
  Platelet counts above 600,000/microL are seen in
  15 to 30 percent of patients.
• A normochromic, normocytic anemia is seen in 45
  and 60 percent of patients.

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disease stage

• The peripheral blood and bone marrow aspirate
  differential count are key components of
  determining the disease stage. In general,
  peripheral blood and bone marrow
• blasts between 10 and 19 percent are diagnostic
  of accelerated phase disease, while
• blasts over 20 percent are diagnostic of blast
  crisis.

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Genetic

• Patients whose cells lack evidence of BCR-ABL1
  gene fusion by FISH or RT-PCR do not have CML

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Leukemoid reaction

•  The peripheral blood count may be as high as
  50,000/microL and can easily mimic CML. However,
  the following features are more commonly found in
  a leukemoid reaction and help to distinguish it
  from CML
• toxic granulation in the neutrophils,
• a high LAP score,
• lack of a "myelocyte bulge", and
• most importantly, the presence of an obvious
  cause for the neutrophilia.
• Bone marrow examination is often not helpful.
• Cytogenetic or molecular testing is definitive
  for CML if the distinction cannot be made
  clinically.

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The accelerated phase

• 10 to 19 percent blasts in the peripheral blood
  or bone marrow
• Peripheral blood basophils 20 percent
• Platelets lt100,000/microL, unrelated to therapy
• Platelets gt1,000,000/microL, unresponsive to
  therapy
• Progressive splenomegaly and increasing white
  cell count, unresponsive to therapy
• Cytogenetic evolution (defined as the development
  of chromosomal abnormalities in addition to the
  Philadelphia chromosome)

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The blastic phase

• 20 percent peripheral blood or bone marrow
  blasts.
• Large foci or clusters of blasts on the bone
  marrow biopsy.
• Presence of extramedullary blastic infiltrates
  (eg, myeloid sarcoma, also known as granulocytic
  sarcoma or chloroma)

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OVERVIEW OF TREATMENT OPTIONS 

• Potential cure with allogeneic hematopoietic cell
  transplantation (HCT)
• Disease control without cure using
  tyrosine kinase inhibitors (TKIs)
• Palliative therapy with cytotoxic agents