Chronic Myelogenius Leukemia

Chronic Myelogenius Chronic Myelogenius LeukemiaLeukemia

• It’s clonal myeloproliferative disease arising from emmatural cells of a myelopoiesis which morphological substrate are mainly maturing and mature granulocytes, basically neutrophils

Possible etiological factorsPossible etiological factors

• Ionising radiation. Ionising radiation.

• Small doses of radiation.Small doses of radiation.

• Weak electromagnetic radiances.Weak electromagnetic radiances.

• Herbicides, insecticides etc.Herbicides, insecticides etc.

• Chemical agents - benzene Chemical agents - benzene

Chronic myelogenous leukemia (CML)

• Adults, usually 40-50• Philadelphia chromosome• Clinical: slow onset, nonspecific symptoms, marked splenomegaly• Lab: leukocytosis (>100,000)

– PMNs, myelocytes, eosinophils, basophils, <5% “blasts”• BM: hypercellular (granulocytic/megakaryocytic)• D/D: leukemoid reaction (↑LAP)• Course: 50% accelerated phase

– ↑ anemia, ↓ PLTs, ++ cytogenetic abn, blastic crisis

In 95% of cases, CML shows a specific chromosome aberration (Philadelphia chromosome with a specific BCR-ABL translocation) and may make the transition into a blast crisis. The formation of the Philadelphia chromosome plays a significantrole in the understanding of the pathogenesis of CML. The main portion of the long arm of chromosome 22is deleted and translocated to the distal end of the long arm of chromosome 9. This results in an elongated chromosome 9 or 9q. A small part of chromosome 9 is then reciprocally translocated to the broken end of22 or 22. This now forms the BCR-ABL hybrid gene, which codes for a 210-kDa protein, or p210, which has increased tyrosine kinase activity.5,8 Tyrosine kinase activity provides an important mediator to regulate metabolic pathways causing abnormal cell cycling. The activation of tyrosine kinase activity may suppress apoptosis (natural cell death) in hematopoietic cells and provide the mechanism for excess cell production

Ph chromosomePh chromosome

BCR-ABLBCR-ABL (activated activated

tyrosine kinase)tyrosine kinase)

BCRBCR ABLABL

CMLCML

The Philadelphia (Ph) Chromosome Leads to CML

bcr

abl

fusion 9abl/bcr

fusion 22bcr/abl

ChronicPhase

AcceleratedPhase

CML

BlastCrisis

STAGING OF CML

Three main stages, determined by percentage of blast cells in the blood

- Chronic Phase- Patient usually diagnosed- Fewer than 10% of cells in blood and bone marrow are blast- Prognosis: (with imatinib) 5yr: 70%, 10yr: 30-40%

- Accelerated Phase- 10-19% of cells in blood or bone marrow are blast, Basophilia ≥ 20%

- Blastic Phase, aka “blast crisis”- Fulminant symptoms of disease, multiple organ involvement- 20-30% or more blasts in bone marrow and blood- Prognosis: UNPROMISING, 2 months, may extend survival with

newer drugs or chemotherapy

Chronic myeloid leukemia

• Laboratory finding – Blood count

• Hb low, WBC raised, platelets low, normal or raised

– Blood film. • Neutrophilia with the whole spectrum of myeloid

precursors including occasional blasts

– Bone marrow aspirate. • Increased cellularity, increased myeloid precursors

– Cytogenetics reveals • t(9;22) translocation (the Philadelphia chromosome)

Numerous granulocytic forms seen here, including immature myeloid cells and bands – CML

Diagnostic criterias of chronical Diagnostic criterias of chronical phase CMLphase CML

• Combined or isolated increasing of a lien and-or a liver.

• The maintenance of leucocytes in peripheric blood more than 80x109/l.

• Alteration in the leukocytic formula to the left with total of myeloblasts and promyelocytes more than 4 %.

• Total of blasts and promyelocytes in an bone marrow more than 8 %..

Unfavorable signs for forecasting of Unfavorable signs for forecasting of survival rate of patients in chronic survival rate of patients in chronic

phase CMLphase CML

- - The lien dimensions ≥ 5 sm from under edge of a costal arch;

- Percent of blast cells in blood ≥ 3 % and-or bone marrow ≥ 5 %;

- Haemoglobin level ≤ 100 g/l;

- Percent of eosinocytes in blood ≥ 4 %..

DIAGNOSTIC CRITERIA OF THE DIAGNOSTIC CRITERIA OF THE PHASE OF THE ACCELERATION.PHASE OF THE ACCELERATION.

• Presence in peripheric blood / a bone marrow of blast cells to 10-29 %

• The sum of blasts and promyelocytes of ≥30 %• Quantity of basophils in blood of ≥20 %• Thrombocytopenia <100 *109/l, not bound to therapy• Augmentation of the sizes of a lien in the course of

therapy (more than on 10 sm)• Additional chromosomal anomalies (an additional Ph-

chromosome, a trisomy of 8th pair, an isochromosome 17, etc.).

Diagnostic criteria blast crisis

• The diagnosis of a blast crisis (BC) is established at presence in peripheric blood or in a bone marrow of blast cells more than 30 % or at appearance of the extramedullary locuses of a hemopoiesis (except a liver and a lien).

• Average duration БК of 3-6 months.

Methods of diagnostics CMLMethods of diagnostics CML..

• Morphological blood analysis and a bone marrow punctate.

• Karyological research of a bone marrow (standard cytogenetic research and a method fluorescent hybridisation in situ-FISH)

• PCR - for diagnostics and monitoring of the minimum residual illness in the course of therapy (revealing chimer BCR-AB α a transcript).

Laboratory findings

1 Leucocytosis is usually >50 x 109/L and sometimes>500 x 109/L (Fig. 13.2). A complete spectrumof myeloid cells is seen in the peripheral blood. The levels of neutrophils and myelocytes exceed those of blast cells and promyelocytes.

2 Increased circulating basophils.3 Normochromic, normocytic anaemia is usual.4 Platelet count may be increased (m.ost frequently), normal or

decreased. 5. Neutrophil alkaline phosphatase score is invariably low. It is raised in

the myeloproliferative diseases and infections.• 6 Bone marrow is hypercellular with granulopoietic• predominance.• 7 Ph chromosome on cytogenetic analysis (conventional• or FISH) of blood or bone marrow (Fig. 13.1).• 8 Serum uric acid is usually raised.

Clinical FeaturesSigns and SymptomsClinical FeaturesSigns and Symptoms

• People with CML may not have any symptoms at the time of diagnosis. They may be diagnosed following a medical examination for another condition or as part of a periodic checkup. CML signs and symptoms tend to develop gradually. Some signs and symptoms of CML are:

• shortness of breath due to anaemia • abdominal discomfort due to splenomegaly • weight loss • fever, sweats, NOT due to infection • headache (occasionally) due to hyperleucocytosis • bruising, epistaxis, menorrhagea, bleeding (uncommon).• Gout • Many of the signs and symptoms for CML are common to other

illnesses. Most people with these signs and symptoms do not have CML

The symptoms of chronic phase CML

• can depend on how high the person's white blood cell count is. Often, people do not notice any symptoms at all. Their CML is found during a routine doctor's visit. Others may have symptoms such as:

• Fatigue (tiredness) • Headache • Pain or a feeling of fullness on the left side of the

abdomen (caused by an enlarged spleen)

Accelerated phase can include

• Fever

• Night sweats

• Weight loss

• Shortness of breath and pale skin caused by anemia (too few red blood cells)

Blast phase

In the blast phase, the number of blasts in the bloodstream grow rapidly. As a result, there are fewer normal blood cells (white blood cells, red blood cells and platelets), and the symptoms listed above become severe. Patients often have problems with bruises, bleeding and infection. When CML is in the blast phase, the disease resembles acute myelogenous leukemia, or in a minority of cases, acute lymphocytic leukemia.

SplenomegalySplenomegaly

At the expressed At the expressed splenomegaly the splenomegaly the liver, but always liver, but always

to a lesser to a lesser degree is usually degree is usually

enlarged also)enlarged also)

The patient in a myelosis The patient in a myelosis terminal-stage.terminal-stage.

Imatinib (Gleevec)

Normal Bcr-Abl Signaling

• The kinase domain activates a substrate protein, eg, PI3 kinase, by phosphorylation

• This activated substrate initiates a signaling cascade culminating in cell proliferation and survival

PP P

ADP P

P

PP P

ATP

SIGNALING

Bcr-Abl

Substrate

Effector

ADP = adenosine diphosphate; ATP = adenosine triphosphate; P = phosphate.Savage and Antman. N Engl J Med. 2002;346:683Scheijen and Griffin. Oncogene. 2002;21:3314.

Imatinib Mesylate Mechanism of Action

• Imatinib mesylate occupies the ATP binding pocket of the Abl kinase domain

• This prevents substrate phosphorylation and signaling

• A lack of signaling inhibits proliferation and survival

P

PP P

ATP

SIGNALING

Imatinib mesylate

Bcr-Abl

Savage and Antman. N Engl J Med. 2002;346:683.

Chronic myeloid leukemia

• Treatment – Chemotherapy

• hydroxyurea

– Tyrosine kinase inhibitors– Interferone α – Stem cell transplantation

• Usage of Tasigna– Too few white

cells and/or platelets

– Changes in liver enzymes

– Changes in pancreatic enzymes

– Nausea – Constipation – Diarrhea – Itching – Rash

Common Treatments• The usage of Gleevec

during the beginning of CML – Swelling from too

much fluid in the body

– Puffiness around the eyes

– Nausea – Vomiting – Muscle cramps – Diarrhea – Rash

• Usage of Sprycel – Too few red cells,

white cells and/or platelets

– Too much fluid in the chest

– Too much fluid in other tissues (edema)

– Diarrhea – Headache – Low calcium levels in

the blood – Slight changes in liver

function.

Chronic lymphogenic Chronic lymphogenic leukemialeukemia

Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes.

causes

- As in the case of most malignancies, the exact cause of CLL is uncertain.

- The protooncogene bcl2 is known to be overexpressed, which leads to suppression of apoptosis (programmed cell death) in the affected lymphoid cells.

- CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare.

Signs and symptomsPatients with CLL present with a wide range of symptoms and signs at presentation. Onset is insidious, and it is not unusual for this disorder to be discovered incidentally after a blood cell count is performed for another reason. Predisposition to repeated infections such as pneumonia, herpes simplex labialis, and herpes zosterEnlarged lymph nodesEarly satiety and/or abdominal discomfort related to an enlarged spleenMucocutaneous bleeding and/or petechiae secondary to thrombocytopeniaTiredness and fatigue secondary to anemia

• Physical: Localized or generalized lymphadenopathy

-Splenomegaly (30-40% of cases)-Hepatomegaly (20% of cases)-Petechiae-Pallor

Staging

• Two staging systems are in common use, the Rai-Sawitsky in the United States and the Binet in Europe. The Rai-Sawitsky staging system divides CLL into 5 Stages, 0-IV.

Stage 0 is lymphocytosis in the blood and marrow only, with a survival of longer than 120 months.

Stage I is lymphocytosis and adenopathy, with a survival of 95 months.

Stage II is lymphocytosis plus splenomegaly and/or hepatomegaly, with a survival of 72 months.

Stage III is lymphocytosis plus anemia (hemoglobin <10 g), with a survival of 30 months.

Stage IV is lymphocytosis plus thrombocytopenia (platelets <100,000), with a survival of 30 months.

Chronic lymphocytic leukemia, autoimmune hemolytic anemia, Kaposi's sarcoma A 70 year old man with a 6-year history of generalized lymphadenopathy, hepatosplenomegaly, hypogammaglobulinemia and recurrent pulmonary infections, undergoing chemotherapy with monthly courses of chlorambucil-methylprednisolone. Four months earlier he became anemic (Ht 24%, reticulocytes 185.000/μL). In the last 3 months he developed a confluent palpable rash on the interior surface of the leg ranging from purple patches in the early lesions to red-brown-blue macules or nodules in the older lesions, with rapid extension. The nodules had a large base and bled easily. The lesions were non-pruritic and painful and the adjacent skin was red and swollen.

• Indolent clinical course• Median survival : 4-6 yrs• Occasional transformation to large non-Hodgkin’s lymphoma

(Richter’s syndrome) --- 3 to 5 %

Chronic Lymphocytic Leukemia (CLL)

lymphocytes

‘smudge’ cells

CLL

Diagnostic criteria of CLLDiagnostic criteria of CLL• Absolute lymphocytosis in bloodAbsolute lymphocytosis in blood• More than 30 More than 30 Treatment• At the time of diagnosis, most patients do not need to be treated with chemotherapy unless they have weight

loss of more than 10%, extreme fatigue, fever related to leukemia, night sweats, progressive marrow failure, autoimmune anemia or thrombocytopenia not responding to prednisone, progressive splenomegaly, massive lymphadenopathy, or progressive lymphocytosis. Progressive lymphocytosis is defined as an increase of greater than 50% in 2 months or a doubling time of less than 6 months.

• Patients at stage 0 whose disease is stable require only periodic follow-up. Early treatment has not been demonstrated to be advantageous. Prednisolone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with autoimmune manifestations of the disease.

Nucleoside analogs (ie, fludarabine, cladribine, and pentostatin) include a new group of drugs with major activity against indolent lymphoid malignancies, including CLL.

- Fludarabine is the most extensively studied and currently is the most commonly used second-line therapy in CLL.

- Responses to treatment with chlorambucil and prednisone are observed in 38-47% of patients. - Patients treated with fludarabine have much higher rates (80%) of overall responses and a 37%

complete remission rate. • Studies using purine analogs, especially fludarabine, compared to alkylator-based therapies

have shown that the response rates are superior and the progression-free interval is longer, but evidence to show prolonged overall survival is premature

• % of lymphocytes in a bone marrow punctate % of lymphocytes in a bone marrow punctate • Immunologic acknowledgement of presence V-kleto-chnogo of a clone of leukemic lymphocytesImmunologic acknowledgement of presence V-kleto-chnogo of a clone of leukemic lymphocytes• Lien and liver augmentation - a facultative signLien and liver augmentation - a facultative sign• Auxiliary diagnostic character of a lymphatic tumoral proliferation - Botkin-Gumprehta cells in a Auxiliary diagnostic character of a lymphatic tumoral proliferation - Botkin-Gumprehta cells in a

blood smear (leukolysis cells represent an artefact: in their liquid blood is not present, they are blood smear (leukolysis cells represent an artefact: in their liquid blood is not present, they are formed in the course of smear preparation)formed in the course of smear preparation)

• ImmunophenotypingImmunophenotypingе, е, for CLLfor CLL presence CDpresence CD - 19, 22, 23 - 19, 22, 23 is characteristic is characteristic

Investigation:

• CBC:– WBC:.– Diff:lymphocytosis ,the

absolute lymphocyte count is>5x109/l and may be up to 300x109/l or.

Blood film:

70-99% of white cells mature lymphocyte.

Smudge or smear cells also present.

Immunophenotyping:

Shows that the lymphocyte are B cells

(CD19) expressing one form of light chain

( or only) cells are also CD5 & CD23+ve.

• Bone marrow aspiration:

Lymphocytic replacement of normal marrow.• Immunoglobulinelectrophoresis: of Ig, more marker with advance disease.• Cytogenetic :

The 4 most common abnormalities are; deletion of13q14,trisomy 12, deletion of 11q23 & structural abnormality of 17p involving the p53 gene.

RaiStaging

CLL

CLL

Marrow

<20%

Lymph-ocytes

Lymphocyte1,500 to 4,000

/uL

NoPalpable

L.N.

NoPalpableDisease

NormalHb

NormalPlatelets

BLO

OD

MARROW

Ab

dom

en

L. N.

Hb.

Plate

let

SURVIVALGOK

CLL

Marrow

>40%

LC

LC>

15,000/uL

NoPalpable

L.N.

NoPalpableDisease

NormalHb

NormalPlatelets

SURVIVAL150

months

Stage “0”

CLL

Marrow

>40%

LC

LC>

15,000/uL

PalpableL.N.

NoPalpableDisease

NormalHb

NormalPlatelets

SURVIVAL101

months

Stage “I”

CLL

Marrow

>40%

LC

LC>

15,000/uL

PalpableL.N.

Hepato-Spleno-megaly

NormalHb

NormalPlatelets

SURVIVAL71

months

Stage “II”

CLL

Marrow

>40%

LC

LC>

15,000/uL

PalpableL.N.


Anemia NormalPlatelets

SURVIVAL19

months

Stage “III”

CLL

Marrow

>40%

LC

LC>

15,000/uL

PalpableL.N.


Anemia Thrombo-cytopenia

SURVIVAL19

months

Stage “IV”

BinetStaging

CLL

CLLGroup A

No anemia or thrombocytopenia, < three of five lymph node areas

Group BNo anemia or thrombocytopenia,

Three or more lymph node areas

Group CAnemia (Hb <10 g/dL) or

Thrombocytopenia (Platelets <100 x 109/L)

AxillaryL.N.

InguinalL.N.

CervicalL.N.

Liver

SpleenBinet Staging of CLL

Complications

- Hypogammaglobinemia and impaired T-cell function associated with CLL predispose patients to potentially serious infections. Patients who demonstrate a pattern of repeated infections, such as pneumonia and septicemia, should be treated monthly with prophylactic parenteral gamma globulin.

- Anemia secondary to bone marrow involvement with CLL, splenic sequestration of red blood cells, and autoimmune hemolytic anemia associated with a positive Coombs test are included in the differential diagnosis of a patient with anemia who has CLL.

- Thrombocytopenia: The causes of low platelets in patients with CLL are very similar to the causes of anemia in patients with CLL and include bone marrow involvement, splenic sequestration, and immune thrombocytopenia.

Treatment• At the time of diagnosis, most patients do not need to be treated with chemotherapy

unless they have weight loss of more than 10%, extreme fatigue, fever related to leukemia, night sweats, progressive marrow failure, autoimmune anemia or thrombocytopenia not responding to prednisone, progressive splenomegaly, massive lymphadenopathy, or progressive lymphocytosis. Progressive lymphocytosis is defined as an increase of greater than 50% in 2 months or a doubling time of less than 6 months.

• Patients at stage 0 whose disease is stable require only periodic follow-up. Early treatment has not been demonstrated to be advantageous. Prednisolone alone, usually in a dose of 20-60 mg daily initially, with subsequent gradual dose reduction, may be useful in patients with autoimmune manifestations of the disease.Nucleoside analogs (ie, fludarabine, cladribine, and pentostatin) include a new group of drugs with major activity against indolent lymphoid malignancies, including CLL.

Fludarabine is the most extensively studied and currently is the most commonly used second-line therapy in CLL.

Responses to treatment with chlorambucil and prednisone are observed in 38-47% of patients.

Patients treated with fludarabine have much higher rates (80%) of overall responses and a 37% complete remission rate.

• Studies using purine analogs, especially fludarabine, compared to alkylator-based therapies have shown that the response rates are superior and the progression-free interval is longer, but evidence to show prolonged overall survival is premature

The combination of fludarabine and cyclophosphamide has shown higher response rates, but direct comparative trials of fludarabine and cyclophosphamide to fludarabine alone are lacking. oThe combination of fludarabine and chlorambucil recently has been shown to result in more infections than either single agent alone.•Various combination regimens have shown improved response rates in several randomized trials but failed to show any survival advantage. Common combination regimens include chlorambucil and corticosteroids; cyclophosphamide, doxorubicin, and prednisone (CAP); cyclophosphamide, vincristine, and prednisone (CVP); and cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP).•Therapy with monoclonal antibodies has been evaluated in patients with CLL. The most useful agent in clinical trials so far appears to be CAMPATH-1H, an antibody directed at CD52. Rituxan (rituximab) also is effective as a second-line or third-line treatment and may assume a more prominent role in the future.Patients with CLL demonstrate autoimmune anemia and or thrombocytopenia up to 25% of the time, and, at the same time, immune incompetence is present, characterized by a progressive profound hypogammaglobulinemia

Chronic Myelogenius Leukemia

Documents

Transcript of Chronic Myelogenius Leukemia