Chronic leukemias

Mohammed Adem

Jimma university

Clinical pharmacy PGYI

mohzum@hotmail.com31,Augest 2011

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Outline

• Definition• Introduction• Epidemiology• Etiology & path physiology• Clinical feature and diagnosis• patient management• Outcome Evaluation

CML then CLL31,Augest 2011

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Chronic leukemias

• when the malignant clone is able to differentiate accumulation of more mature cells of the affected cell type.

• Differs from acute in that its clinical course is indolent. Most are asymptomatic at presentation

• survive for several yrs after their initial Dx, even without Rx.

• In certain CL evolution in to acute d/se may occur, which may need d/t mgt approach.

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Chronic leukemias…Include:

hairy cell leukemia, and

prolymphocytic leukemia.

CML,CLL,

.

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CML

Is a hematologic cancer that results from an abnormal

proliferation of an early myeloid progenitor cell.

Results in abnormal proliferation and accumulation of

progenic cell ,mature myeloid cells, erythroid compartment

and platelets in the bone marrow& peripheral blood

• The cytogenic hall mark Ph chromosome (9:22) in up to

95%

BCR gene on chrom 22q11-ABL gene on chrom9q34. 531,Augest 2011

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CML…• The clinical course has 3 phases: chronic phase,

accelerated phase, and blast phase/crisis.

• The disease begins in the chronic phase in which s/s can be controlled with chemotherapy.

• Then progresses to a transition phase, known as accelerated phase, in w/c blast counts in the bone marrow and peripheral blood increase despite ongoing therapy.

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CML…

• Finally, there is blast crisis, a terminal phase that is similar to acute leukemia that can lead to rapid clinical deterioration and death.

• Why transition? poorly understood.• 85 to 90% present in the chronic phase. • Today this evolution into the accelerated& blastic

phases can be delayed if not prevented/cured

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Epidemiology

• The incidence of CML is 1.5 per 100,000 people/yr.

• 1/5th of all cases of leukemia in the US. • The commonest leukemia in Africa& Ethiopia.• uncommon in children and adolescents

• Median age at presentation is 70-80. • Common male

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Etiology

• The cause is unclear• No familial association of CML has been noted..• Benzene exposure does not inc. the risk of CML but AML.• Is not associated with any known oncogenic viruses

• smoking can accelerate the progression to blast crisis in pre-imatinib era.

• CML is not a frequent 2dry leukemia after Rx of other cancers with radiation or anti-CA agents or both.

• Ionizing radiation in high doses is the only known risk factor for CML.

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Pathogenesis

Genetic abnormality

The product of the fusion gene plays a central role in the dev’t of CML.

The oncogene BCR-ABL encodes an enzyme tyrosine phosphokinase (usually p210).Through this chromosomal translocation, the ABL protooncogene is able to escape the normal genetic controls on its expression and is activated into a functional oncogene p210BCR-ABL

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Pathogenesis…

• The attachment of the BCR sequences to ABL results in:

• p210BCR-ABL is constantly active, and this unregulated activity results in cell proliferation, inhibition of apoptosis, and accumulation of the malignant clone.

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Pathogenesis… Hematopoietic abnormality

Expansion of granulocytic progenitors and a decreased sensitivity of the progenitors to regulation increased white cell count

Megakaryocytopoiesis /plt is often expanded

Erythropoiesis is usually deficient

Function of the neutrophils and platelet is nearly normal

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Clinical Presentations

approximately 70% of patients are asymptomatic at the time of Dx. • Sx related to hyper metabolism:

weight loss, lassitude, anorexia or night sweats• platelet dysfunction.

Bruising ,epistaxis, menorrhagia or hemorrhage from any site.• Anemia.

• Organ infiltration:

Splenomegally early satiety , LUQ pain/massOther Sx

Urticaria,visual disturbance, Unexplained fever , bone and joint pain ,thrombosis such as vasoocclusive disease, CVA,MI .

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Physical Findings

• Splenomegaly :the most common physical finding (> 90%)• Mild hepatomegaly ( occasionally).

• Persistent splenomegaly despite continued therapy is a sign of disease acceleration.

• Lymphadenopathy and myeloid sarcomas are unusual except late in the course of the disease; when present the prognosis is poor.

• Bruising , Fever, Bleeding (gingivae most common)

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Laboratory and Radiographic Work-up:

• CBC with manual differential• Leukocyte alkaline phosphatase• Uric acid level• Cytogenetic study: Ph chromosome• Bone marrow biopsy• organ functions

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Lab feature… Lab feature in Stable/chronic phase CML1. CBC

RBC a mild degree of NCNC anemia

Leukocytosis (WBC >100 × 103 /µL, or 100 × 109/L). Usually <5% circulating blasts

+/- Basophilia, eosiophilia

Thrombocytosis ( ~50% of patients in chronic phase)

2. Phagocytic functions of neutrophil are usually normal17Mohammed A

3. Bone marrow or chromosomal findings

Hypercellularity with presence of blasts Presence of Ph/ shortened chromsome increased myeloid to erythroid ratio

4. Other basic studies;

organ function, uric acid…

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Lab feature…

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Prognostic Factors

• The clinical outcome of patients with CML is variable• Before imatinib era, expect death 10% of pts within 2 years

and in about 20% yrly thereafter, and the median survival time was ~4 years

Sokal system• percentage of circulating blasts, • spleen size, • platelet count, • age, and • cytogenetic clonal evolution

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Treatment of CML

Desired Outcome

complete hematologic remission. early goal.

complete Cytogenetic remission. Elimination of ph.

complete molecular remission. ????RT-PCR -tive

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Treatment…Nonpharmacologic Therapy

Allogeneic Stem Cell Transplantation• Is the only curative treatment option for CML.• It is an option for younger pts (younger than 50 yrs)• Cure rates are superior when pts are transplanted in

chronic phase within the 1st yr of dx and may be as high as 70%.

• significant risks10% to 20% early mortality (100 days).

Splenectomy Leukapheresis

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Nonpharmacologic...Leukapheresis

Useful in emergencies where leukostasis-related complications such as pulmonary failure or cerebrovascular accidents are likely.

Possible role in the treatment of pregnant women in whom it is important to avoid potentially teratogenic drugs

Splenectomy painful splenomegaly unresponsive to chemotherapy or

hypersplenism Does not influence survival but improves certain aspects of

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Outcome of SCT depends on:

• the patient (e.g., age and phase of disease);

• the type of donor [e.g., syngeneic (monozygotic twins) or HLA-compatible allogeneic, related or unrelated];

• the preparative regimen (myeloblative or reduced intensity);

• posttransplantation treatment.

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Treatment…Pharmacologic Therapy

The success of therapy depends in part on the clinical phase of the disease.

I. tyrosine kinase inhibitors:

Imatinib mesylate (Gleevec). 1st line 400mg/d, 600-800mg/d

induces CHR in more than 97%. 6wks

CCR in about 76% of pts in chronic phase. 9-12months

Most pts have traces of the d/se when measured by RT-PCR &are not cured of their d/se. CMR 7%

Progression to other phases is 3%. Then <1%24Mohammed A

Treatment…

II. an alternative therapy

for patients who do not respond to imatinib and

are not candidates for stem cell transplantation.

Nilotinib (400mg bid) , Dasatinib (100mg/d)

.

Interferon-α & Cytarabine.

Conventional chemotherapy {hydroxyurea* or busulphan}

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Clinical data Allogeneic SCT can be considered for pts with

accelerated/blastic phases or who fails to respond to imatinib.

imatinib (400 mg/d) is more effective than IFN- and cytarabine. CHR and CCR rate, at 18 months with imatinib was 97%

and 76% compared to IFN and Cytarabine.(69% and 40% respectively).

Cyclophosphamide +total-body irradiation had more complications(hospital admision and stay) compared to Cyclophosphamide+ Busulfan.

If no any CR following six months of imatinib are unlikely to achieve major MR and other t/t approaches should be offered .

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IFN-α 1–3 mu SC 3 xwk, increasing to daily as tolerated

Before imatinib, when allogeneic SCT was not feasible. Only longer follow-up of patients treated with imatinib will

prove whether IFN- consideration. With availability of TKIs, it is now offered only if all other

options have failed

Hydroxyurea induces rapid disease control 1–4 g/d to be halved with each 50% reduction of the

WBC. cytogenetic remissions are uncommon

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Clinical data...

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Busulphan• acts on early progenitor cells, has a more prolonged

effect.

• not recommended due to its serious A/Es:

Unexpected &occasionally fatal myelosuppression in 5–10%

Endocardial; Marrow and Pulmonary fibrosis Addison-like wasting syndrome; Obstructive bronchiolitis ,Alopecia

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Clinical data...

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Rx of accelerated phase

Is similar to stable/chronic phase of CML

Rx of Blast Crisis• Rx is generally ineffective and depends on the

phenotype blast cells.• AML/ALL treatment protocol.

imatinib poor response.(HR 21%). In 52% of patients

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STG of Ethiopia

General Rx

Symptomatic anaemia, dehydration and electrolyte if present Allopurinol, 100 mg P.O. TID should be started before the

initiation of specific treatment

Chemotherapy• Hydroxyurea p.o 2 to 4 g/day initially .depending on the cell

count. withheld if the WBC count < 10,000/L• Busulphan, 4 to 8mg/day .stopped when the WBC count

below 20,000/L.

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Outcome Evaluation

Monitor for complications of disease and treatment & for relapse.

• HR at 3 months.• CR at 9 to 12 months.• MR/ bcr-abl transcripts is currently the best

available test to monitor d/se response. Q 3month

• ADR and manage accordingly• ddI imatinibe (cyp3A4,fluid retention)

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Take a Break !…

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Chronic lymphocytic leukemia

or

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Chronic lymphocytic leukemia

A cancer of lymphoid cells with primary involvement of bone marrow and blood. lymph nodes, and spleen.

In most cases, the cells are monoclonal B lymphocytes (95% ) that are CD5+

T cell CLL can occur rarely. The main feature is a progressive accumulation of

functionally incompetent, long-lived lymphocytes

considered to be due to decreased apoptosis rather than increased proliferation.

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Epidemiology

• is the most prevalent form of leukemia in western countries.

• 1/3rd of all cases and is 2x as CML.• most frequently in older adults and is exceedingly

rare in children. Age of presentation 70 years.

• More common in white persons than in African Americans. M:F 2:1

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Etiology • The specific aetiology of CLL is unknown.

• Genetic factors play a role in high incidence of CLL in some families.

Chromosomal abnormalities deletion at 13q14 (50%).• No established viral etiology.

• No definite leukemogenic role of environmental factors chemicals, including benzene, exposure to Ionizing radiation and virus.

• There is inc. incidence in farmers (???role of herbicides or pesticides) rubber manufacturing workers, asbestos workers, and tire repair workers

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Pathogenesis Cell of Origin

The exact cell of origin is controversial but has been described as an antigen-activated B lymphocyte.

• The normal T cell to B cell ratio is reversed in CLL where nearly 90% of all lymphocytes are B cells.

• Monoclonal lymphocytes accumulate in the

peripheral blood, bone marrow, lymphoid tissues, and sometimes other organs.

• Infiltration of the bone marrow may eventually result in pancytopenia( too few cells)

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Pathologyimmunodeficiency

I. Deficiency of normal B cells often leads to bacterial infection.

II. The absolute number of T cells may vary But the function is invariably abnormal.

III. Defective regulation of T-cell immunity leads to chronic inflammation.

IV. Regulatory mechanisms normally control and terminate T cell activation.

V. however, these mechanisms fail leading to chronic T cell activation and subsequently to inflammation

Hypogammagloblenimia. • Dysfunctional antibody generation by the incompetent

malignant and normal B cells under the dysregulation of aberrant T cells.

Infection risks……

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Autoimmunity ..• Frequent autoimmune complications in CLL and

due to antibodies restricted to hematopoietic/ blood cell

• Autoimmune hemolytic anemia occurs in 10% to 25% of cases at some time during the course.

• Autoimmune thrombocytopenia (2%)

• Pure red cell aplasia (dec cell growth). <1%

• Autoimmune neutropenia (< 1%).

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PathologyAutoimmunity

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Clinical presentations

• Approximately 40% are asymptomatic at dx.

Often found incidentally when a CBC is done for another reason.

• In symptomatic cases complaint is features of anemia, Easy bruising/Gingival bleeding, Thrombocytopenia.Organomegaly, bone pain ;Flank pain; generalized itching Lymphadenopathy when present as lymphoma.Frequent infections. CLL weakens B cell immunity

• B symptoms are not common at dx.Mohammed A

Careful Hx and PE

Diagnostic testings• CBC• Peripheral blood smear• Bone marrow biopsy• Cytogenetic studies/Immunophenotyping.• Molecular testing/Cytometry• Imaging studies of the chest and abdomen,pelvis• major organ function test RFT,HFT, electrolytes

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Diagnosis

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The diagnostic criteria for CLL

A. A peripheral blood lymphocyte count of greater than >5 × 109/L; usually >10 × 109/L.

B. presence of B cell-specific antigens CD5(+) . C. A bone marrow aspirates showing greater >30%

lymphocytes

D. A patient presenting with an autoimmune hemolytic anemia or autoimmune thrombocytopenia. B-cells CLL

E. Findings may include hypogammaglobulinemia, hypergammaglobulinemia, or monoclonal gammopathy.

F.

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Staging of Typical B Cell Lymphoid LeukaemiaStage Clinical Features Median Survival, Years

RAI System 

0. Low risk Lymphocytosis only in blood and marrow >10

I: Intermediate risk Lymphocytosis + lymphadenopathy 7

II Intermediate risk  Lymphocytosis + splenomegaly /hepatomegaly  

III: High risk Lymphocytosis + anemia 1.5

IV High risk Lymphocytosis + thrombocytopenia

Binet System 

A Fewer than 3 areas of clinical lymphadenopathy. no anemia or thrombocytopenia

>10

B Three or more involved node areas; no anemia or thrombocytopenia

7

C Hemoglobin 10 g/dL and/or platelets <100,000/L

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• Advanced Rai or Binet stage

• Lymphocytosis

• Splenomegaly/Hepatomegaly; Lymphadenopathy

• Anemia; Thrombocytopenia• Diffuse marrow histology

• Poor response to chemotherapy

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Poor prognostic factors

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Treatment

Desired Outcome

provide palliation of symptoms and improve overall survival.

Reduction in tumor burden and improvement in d/se Sx

Resolution of lymphadenopathy and organomegaly Normalization of peripheral blood counts,

Elimination of lymphoblasts in the bone marrow.

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Nonpharmacologic Therapy

Stem cell transplantation.

Offers longer d/s free remissions

Early mortality after transplant is as high as 40% in CLL.

Mortality can be dec by reducing its intensity but

unclear whether it will produce long-term disease-free survival.

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Treatment...

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Treatment...

Pharmacologic Therapy

Single-Agent Chemotherapy

1. purine analog: fludarabine

2. an alkylating agent: chlorambucil (Leukeran®)

3. Monoclonal Antibodies: Rituximab

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Treatment...

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Treatment...Fludarabine

fludarabine based chemotherapy is used as first-line therapy for younger patients.

is superior to chlorambucil in achieving higher

response rates and producing a longer duration of response.

is effective in previously untreated pts, as well as in pts who have chlorambucil-resistant d/se.

The most commonly used dose is 20 mg/m2 iv daily for 5 consecutive days. every 4 weeks .

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Treatment...

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Treatment...

Chlorambucil• can be taken daily po tabs 4 -10 mg/day. to a

single dose of 40–80 mg every 3–4 weeks

• The ease of administration and limited S/Es make it practical option for symptomatic elderly pts who require palliative therapy.

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Treatment...

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Treatment...Rituximab

• directed against the CD20 molecule on B lymphocytes.

• Alone can induce partial responses in untreated and previously treated CLL patients.

• 3 times weekly for 4 weeks rather than once weekly

• higher doses are required than those used in non-Hodgkin’s lymphoma.

• however, the typical 375 mg/m2 dose is still used commonly50

Treatment...

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Treatment...

Combination Therapy. The combination of fludarabine, cyclophosphamide, and

rituximab is supperior compared with fludarabine alone.

Cyclophosphamide 250 mg/m2 + fludarabine)

complete responses in 69% of patients

molecular remissions in 50% of the cases

Regimen used in other lymphomas CVP ;CHOP

but at the expense of increased infections.

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Treatment...

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Treatment...

• Associated conditions should be managed independently of specific antileukemia therapy.

• Steroids therapy for autoimmune cytopenias and

• Immunoglobulin replacement for patients with hypogammaglobulinemia. in the setting of serious infection

• Antibiotics

• Blood products• Radiotherapy, Splenectomy

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Treatment...

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General• Early stage and asymptomatic d/se should be observed w/o t

Rx.• Infections, if present, should be treated aggressively• symptomatic anemia should be transfused packed RBC.• Allopurinol, 100mg P.O.TID is given before the initiation of

specific Rx.

First line • Chlorambucil, 0.1 to 0.2mg/kg P.O. QD for 3 to 6 weeks. 15

-30mg/m2 P.O. may be given over 3 - 4 days every 14 -21 days. PLUS

• Prednisolone, 0.5-1mg/kg may be added. OR• Cyclophosphamide, 2 -4 mg/kg P.O daily PLUS Prednisolone

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STG of Ethiopia

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Outcome Evaluation• Reduction of malignant lymphocytes.

• Stage of the disease• Response to treatment and possible relapse• Regular follow-up throughout treatment ;Since CLL is not a

curable d/se, palliation of Sx is a reasonable goal in older pts, and

• Aggressive therapies are reserved for younger pts with high-risk CLL.

• ADRs

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REFERENCES

Joseph T. Dipiro et.al; Pharmacotherapy, pathophysiologic approach, 7th edition.

Pharmacotherapy principle and practice, 2007

Harrison’s Principle of Internal Medicine,17th ed.2008.

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Thank you

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Questions???? 31,Augest 2011

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