Chronic Lymphocytic Leukemia

CLL

Definition

CLL: is a monoclonal neoplastic disorder

characterized by a progressive accumulation of functionally incompetent lymphocytes.

Epidemiology

It is the most common form of leukemia found in adults in Western countries.(33% of Leuk)It is a disease of elderly (>60y).

Male: Female = 2:1

Etiology

Cause – unknown ?Herbicides – farmers (pesticides)

Familial clustering – 1st degree relatives 2-4x popAbnormal karyotype is observed in the majority of patients with CLL. The most common

abnormality is deletion of 13q .Trisomy 12, which is observed in 15%Deletion in the short arm of chromosome 17

Types1.The cells of origin in most patients(95%) with CLL

are clonal B cells arrested in the differentiation pathway, intermediate between pre-B cells and mature B cells. Morphologically, in the peripheral blood, these cells resemble mature lymphocytes.

2 .Approximately 2-5% of patients with CLL exhibit a T-cell phenotype .

Clinical ManifestationsPatients present with a wide range of symptoms and signs .

Onset is insidious, and it is not unusual for CLL to be discovered incidentally after a blood cell count is performed for another reason; 25-50% of patients will be

asymptomatic at time of presentation .Enlarged lymph nodes are the most common presenting symptom, seen in 87%

of patients symptomatic at time of diagnosis .A predisposition to repeated infections such as pneumonia, herpes simplex

labialis, and herpes zoster may be noted .Early satiety and/or abdominal discomfort may be related to an enlarged spleen .

Mucocutaneous bleeding and/or petechiae may be due to thrombocytopenia. Tiredness and fatigue may be present secondary to anemia; 10% of patients

with CLL will present with an autoimmune hemolytic anemia .Richter syndrome or Richter transformation refers to the transformation of CLL into an aggressive large B-cell lymphoma and is seen in approximately 3-10% of cases. Patients will often present with symptoms of weight loss, fevers, night sweats, muscle wasting, (ie, B symptoms) and increasing hepatosplenomegaly and lymphadenopathy. Treatment remains challenging

and prognosis poor, with median survival in months .

Physical Signs

In addition to localized or generalized lymphadenopathy, patients may manifest the following:

Splenomegaly (30-54% of cases)Hepatomegaly (10-20% of cases)PetechiaePallor

Lab

Complete blood count (CBC) with differential shows absolute lymphocytosis, with more than 5000 B-lymphocytes/µL. Lymphocytosis must

persist for longer than 3 months .*Clonality must be confirmed by flow cytometry .

*The presence of a cytopenia caused by clonal bone marrow involvement establishes the diagnosis of CLL regardless of the peripheral B-

lymphocyte count .

Blood Film

Microscopic examination of the peripheral blood smear is indicated to confirm lymphocytosis. It usually shows the presence of smudge cells, which are artifacts from lymphocytes

damaged during the slide preparation .NN AnAIHA (reticulocytosis)ITP (thrombocytopenia)

InvxFlow cytometry: is the most valuable test to confirm a diagnosis of CLL. It confirms the presence of circulating clonal B-lymphocytes

expressing CD5, CD19, CD20, CD 23 .Serum quantitative immunoglobulin levels in patients developing repeated infections, because monthly intravenous immunoglobulin administration in patients with low levels of immunoglobulin G (IgG) (< 500 mg) may be beneficial in reducing the frequency of infectious

episodes .

Invx-contBone marrow aspiration and biopsy with flow cytometry is not required in all cases of CLL. However, it may be necessary in selected cases to establish the diagnosis and to assess other

complicating features such as anemia and thrombocytopenia .Liver/spleen ultrasonographic studies may demonstrate

splenomegaly in patients with CLL .CT scanning of the chest, abdomen, or pelvis is generally not required for staging purposes in CLL. However, be careful to not miss lesions such as obstructive uropathy or airway obstruction that are caused by lymph node compression on organs or internal structures.

Serum free light chain (FLC) assays remain a research tool. Monoclonal and polyclonal abnormalities have been detected in half the patients and appear to be associated with poor time to first treatment

Staging

Two staging systems are in common use for CLL :The modified Rai staging in the United States and The

Binet staging in Europe .Neither is completely satisfactory, and both have often

been modified .Because of its historical precedent and wide use, the Rai-Sawitsky system is described first, followed by the Binet .

These systems have been unable to provide information regarding disease progression due to its heterogeneity.

Rai SystemThe original 5-stage Rai-Sawitsky staging system was

revised in 1987 to a simpler 3-stage system .The revised Rai staging system divides patients into low-,

intermediate-, and high-risk groups, as follows :Low risk (formerly stage 0) – Lymphocytosis in the blood and marrow only (25% of presenting population)

Intermediate risk (formerly stages I and II) – Lymphocytosis with enlarged nodes in any site or splenomegaly or hepatomegaly (50% of presentation)

High risk (formerly stages III and IV) – Lymphocytosis with disease-related anemia (hemoglobin < 11 g/dL) or thrombocytopenia (platelets < 100 x 109/L) (25% of all patients)

BinetThe Binet stages are as follows:

Stage A – Hemoglobin greater than or equal to 10 g/dL, platelets greater than or equal to 100 × 109/L, and fewer than 3 lymph node areas involved.

Stage B – Hemoglobin and platelet levels as in stage A and 3 or more lymph node areas involved or hepatomegaly or splenomegalyStage C – Hemoglobin less than 10 g/dL or platelets less than 100 × 109/L, or bothAfter successful treatment of immune cytopenias, CLL may be down-staged

ComplicationsWeight loss of more than 10% over 6 monthsExtreme fatigueFever related to leukemia for longer than 2 weeksNight sweats for longer than 1 monthProgressive marrow failure (anemia or thrombocytopenia)Autoimmune anemia or thrombocytopenia not responding to glucocorticoidsProgressive or symptomatic splenomegalyMassive or symptomatic lymphadenopathyProgressive lymphocytosis, as defined by an increase of > 50% in 2 months or a doubling time of less than 6 months Richter’s syndrome Hypogammaglobulinemia – infections (sinopulmonary)

Autoimmune Manifestations

Autoimmune manifestations in CLL are myriad, as follows : *Positive Coombs test without autoimmune hemolytic anemia

(AIHA) *AIHA

*Immune thrombocytopenia (ITP) *Pure red cell aplasia

*Autoimmune neutropenia *Cold agglutinin disease

*Paraneoplastic pemphigus *Neuropathies

*Evans syndrome

DD

Acute Lymphoblastic Leukemia

Hairy Cell Leukemia

, Lymphoma Diffuse Large Cell

, Lymphoma Follicular

, Lymphoma Lymphoblastic

, Lymphoma Mantle Cell

, -Lymphoma Non Hodgkin

Small Lymphocytic Lymphoma

Treatment

*Patients with CLL do not need to be treated with chemotherapy until they become symptomatic or

display evidence of rapid progression of disease . *Patients with low-risk (Binet A) disease whose CLL

is stable require only periodic follow-up . *In multiple studies and a meta-analysis, early

initiation of chemotherapy has failed to show benefit in CLL; indeed, it may increase mortality .

Ttt-cont

*A variety of chemotherapy regimens are used in CLL. These may include nucleoside analogues, alkylating

agents, and biologics, often in combination . *Allogeneic stem cell transplantation is the only known

curative therapy. The complete response (CR) is defined by absence of lymphocytosis, lymphadenopathy, and

organomegaly without significant cytopenias . *Patients with CLL are prone to infections, both common

and unusual. Pneumococcal and influenza vaccines are recommended.

Ttt- chemotherapy

1 .Chlorambucil - ± PDNis still used as first-line in elderly, fragile populations in

Europe, which make up the bulk of true CLL cases .In the CLL5 study comparing fludarabine with chlorambucil (median age 70 y), while there was significantly higher response rate with fludarabine, progression-free survival was similar (19 vs 18 mo). Overall survival was not significantly affected either, although it was 46 months with fludarabine

compared with 64 months for chlorambucil

Ttt- contNucleoside analogues

constitute a class of drugs with major activity against indolent lymphoid malignancies, including CLL.

Agents in this class include fludarabine, cladribine, and pentostatin .

Fludarabine is the most extensively studied of these nucleoside analogues and is currently the most

commonly used first-line therapy in CLL .It should be noted that many clinical trials in CLL represent a younger population, which can tolerate aggressive chemotherapy regimens to

show impressive results .

ttt

Common combination regimens include the following :Fludarabine, cyclophosphamide, and rituximab (FCR)Pentostatin, cyclophosphamide, and rituximab (PCR)Fludarabine, cyclophosphamide, and mitoxantrone (FCM)Cyclophosphamide, vincristine, and prednisone (CVP)Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)

ttt

Alemtuzumabis a monoclonal antibody directed at CD52 that is approved for use in CLL as both a first-line agent and for salvage in patients with

fludarabine-refractory disease .It has been shown to be effective in treating CLL with p53 mutations [del(17p13.1)].

ttt

Ofatumumab (Arzerra) is a new anti-CD20 monoclonal fully humanized

antibody. It has been approved by US Food and Drug Administration (FDA) for the treatment of patients with CLL refractory to fludarabine and alemtuzumab

Lenalidomide

Lenalidomide is an immunomodulatory drug currently approved for use in multiple myeloma and myelodysplastic syndrome with deletion of chromosome 5q. Studies have utilized this medication in treatment of patients with relapsed and refractory CLL.

Response rates of 47-38% with complete response rates of 9% and elimination of MRD have also been reported.

Corticosteroids

*With chemotherapy. *Control autoimmune manifestations (AIHA &

ITP).

IVIG

Intravenous Immunoglobulin (IVIG): *Combat infections.

*ITP treatment .

BMT

Allogeneic stem cell transplantation is the only known curative therapy. The optimal timing of transplantation is still being investigated ; however, it is known that delay of transplantation until development of refractory disease results in worse outcomes. However, remember that most patients are elderly and too fragile to consider upfront stem-cell transplantation in first clinical remission.

Others

*Allopurinol. *Leukapheresis.

Splenectomy

For Hypersplenism causing cytopenias.

Hairy Cell Leukemia (HCL) Is a chronic lymphoid leukemia that was originally

described in 1958 by Bouroncle and colleagues.Hairy cell leukemia is a B-cell disease, and the abnormal cell has hairlike cytoplasmic projections on its surface.

Hairy cell leukemia is recognized as a clonal B-cell malignancy as identified by immunoglobulin gene rearrangements that result in a phenotype B-cell expression of surface antigens, which reflect the differentiation between the immature B-cell of chronic lymphocytic leukemia and the plasma cell of multiple myeloma.

EpidIs relatively uncommon and accounts for 2% of all

leukemia cases .Some geographic variations have been observed with hairy cell leukemia, such as an extremely low incidence in Japan.

Hairy cell leukemia is observed mostly in males, with a male-to-female ratio of 4:1 to 5:1 .

Hairy cell leukemia occurs predominantly in middle-aged men, with a median age of 52 years.

ManifestationsThe most common symptoms and presenting complaints in hairy cell leukemia are

weakness and fatigue due to anemia .Approximately one third of patients have bleeding from thrombocytopenia, and

another one third have fever and infections from neutropenia .Symptoms related to organ infiltration of the reticuloendothelial system may occur. Abdominal discomfort from an enlarged spleen is present in one quarter

of patients .Some patients may present with weight loss, fever, and night sweats, similar to

other lymphoproliferative disorders.Hairy cell leukemia is associated with gram-positive and gram-negative bacterial

infections, as well as atypical mycobacterial and invasive fungal infections .Other opportunistic infections, such as Legionella, toxoplasmosis, and listeriosis,

have been reported .Hairy cell leukemia is associated with other systemic immunologic disorders including scleroderma, polymyositis, polyarteritis nodosa, erythematous

maculopapules, and pyoderma gangrenosum .Other uncommon conditions may be associated with hairy cell leukemia, such as acquired factor VIII antibodies, paraproteinemia, and systemic mast cell

disease .

SignsSplenomegaly is the most common physical finding in virtually every patient with hairy cell leukemia, and it is massive in more

than 80% of patients .Hepatomegaly with mild liver function abnormalities is found in 20% of cases, and lymphadenopathy is found in 10%.

A low-grade fever is part of the disease, but it may be due to an infection from the resulting neutropenia. In more than half of the cases, it is from a gram-negative organism. Atypical mycobacterial infections are common. Disseminated fungal infections and Pneumocystis carinii may occur in some cases of

hairy cell leukemia .Peripheral lymphadenopathy is uncommon, with fewer than 10% of patients presenting with peripheral nodes larger than 2 cm in diameter. However, internal adenopathy may develop after a prolonged disease course and was found in 75% of patients at

autopsy .

LabThe typical hairy cells of hairy cell leukemia are so named because of their characteristic cytoplasmic projections, which appear as fine (hairlike) microvilli when seen by light microscopy, phase-contrast

microscopy, and electron microscopy .These are mononuclear cells with eccentric or centrally placed nuclei .

Hairy cells have a mature B-cell phenotype and typically express single or multiple immunoglobulin light chains and pan–B-cell antigens, such as CD19, CD20, CD22, and CD79b, but not CD21 (late B-cell marker). The cells also typically express CD103, CD11c, and CD25 but usually not CD5, CD10, or CD23. Hairy cells strongly express CD45, seen as a bright signal, with increased forward and side scatter resembling large lymphocytes and monocytes. Immunophenotypic analysis helps distinguish hairy cell leukemia from other low-grade B-cell

malignancies .Hairy cells can be identified immunophenotypically in 92% of cases, even

when the cells represent less than 1% of the circulating lymphocytes .

Cytochemical evaluation is important for diagnostic confirmation of the morphologic findings. Hairy cells demonstrate strong positivity for tartrate-resistant

acid phosphatase (TRAP) staining .A positive TRAP stain in conjunction with a characteristic bone marrow biopsy is essentially

diagnostic of hairy cell leukemia .The peripheral blood cell counts show pancytopenia

with decreased cell counts in all 3 cell lines .Anemia is usually severe and normochromic-normocytic in character.

Neutropenia and monocytopenia are usually present in hairy cell leukemia, but an elevated white blood cell count

(hairy cells) is found in 20% of cases .Thrombocytopenia is found in more than 80% of patients.

LabThe bone marrow aspirate is usually unsuccessful due to a "dry tap.” Infiltration of the bone marrow by hairy cell

leukemia makes aspirating cells through a needle difficult .Core biopsy of the bone marrow shows a pattern of hairy cell infiltration with a single round or oval nucleus separated by abundant cytoplasm in a fine fibrillar network.

The cell appears separated, resulting in the characteristic fried-egg appearance.

Clonal cytogenetic abnormalities are present in two thirds of patients, and the involvement of chromosomes 1, 2, 5, 6, 11, 14, 19, and 20 have been described. Chromosome 5 abnormality is most frequent (in 40% of patients) with trisomy 5 and pericentric inversions and interstitial

deletions of band 5q13 .

TreatmentThe first-line therapy for hairy cell leukemia is

2-chlorodeoxyadenosine (2-CdA) (Cladribine, Leustatin) 0.1 mg/kg/d by continuous intravenous infusion for 7 days, which

can be performed on an outpatient basis with a pump, using a percutaneous intravenous central catheter (PICC).

Growth factors are not routinely given but may be added in patients with febrile neutropenia. The response is usually first observed in the platelet counts (in 2-4 wk) followed by white blood cell counts and neutrophils and, finally, hemoglobin

levels .Bone marrow biopsy is repeated in 3 months, but minimal

residual disease does not need therapy .IFN- α Splenectomy

CLL

Chronic Lymphocytic Leukemia