Chronic Leukemia

Amaylia Oehadian
 Chronic Leukemia
• Chronic leukemia:
– Chronic myelocytic leukemia
– Chronic lymphocytic leukemia
Chronic lymphocytic leukemia
(CLL)
Chronic lymphocytic leukemia (CLL)

• Hematologic malignancy with characteristic of

mature lymphocyte accumulation in blood, bone
marrow, lymph node and spleen
• Most common type of leukemia in Western
countries
• Rare in Asians
• 90% > 50 years
• Men : women = 2:1
 CLL : etiology

• Genetic
• Immunologic :
– Inherited and acquired immunodeficiency syndrome
• Chromosomes, oncogenes and viruses
– Abnormalities of 13q, trisomy 12
– Deletion/mutation of 17q13 : p53 supressor gene
 CLL : clinical manifestation

• In 25 % patients, CLL is asymptomatic

• Chronic fatique
• Anemia
• Fever
• Bruising
• Weight loss
• Lymphadenopathy
• Splenonegaly
• Hepatomegaly
 CLL : clinical manifestation

• Pulmonary leukemic infiltrates , pleural effusion

( late course)
• Skin involvement
• Infection:
– Herpes zoster
– Bacterial : S.pneumonia, S. aureus,
H.influenzae
– Pneumocyctis carinii
 CLL : laboratory

• Peripheral blood morphology :

– Erythrocytes : normochromic,normocytic ,
hemolysis
– Leukocytes : small mature lymphocytes,
easily ruptured : basket / smudge cells
– Platelet : normal or thrombocytopenia
• Bone marrow:
– Lymphoid infiltration ( nodular, interstitial or
diffuse) > 30 %
 CLL : laboratory
• Hemoglobin : anemia may be caused by :
– Lymphocytes infiltration of the bone marrow
– Hypersplenism
– Autoimmune hemolysis : Coombs’ test (+)
• Lymphocytes
– 10,000 – 200,000/ml, may exceed 500,000/ml
 CLL : laboratory

• Granulocytes
– Normal or increased
• Platelet : thrombocytopenia may be
caused by :
– Bone marrow infiltration
– Hypersplenism
– Immune thrombocytopenia
CLL : mature lymphocytes
CLL : Smudge cell
 CLL : Diagnostic criteria
(CLL Working group, International CLL Workshop,
National Cancer Institute Working Group)

1. Persistent elevation of peripheral blood

lymhocytes > 10,000/mm3 , with predominant
mature lymphocytes
2. Bone marrow aspiration : lymphocytes > 30 %
3. Peripheral blood lymphocytes are monoclonal
B lymphocytes

Diagnosis : 1 + 2 or 1 + 3
2 + 3 , if lymphocytes < 10,000/mm3
 CLL : differential diagnosis

• Benign causes of lymphocytosis

– Viral infection : hepatitis, CMV, EBV
– Bacterial infection : brucellosis, thyphoid fever, tbc
– Autoimmune disease
– Drug and allergic reaction
– Thyrotoxicosis and adrenal insufficiency
– Post splenectomy
• Hairy cell leukemia
• Cutaneous T-cell lymphoma
• Leukemic phase of non-Hodgkin lymphoma
• Prolymphocytic leukemia
 CLL : Stage ( modified Rai)
Stage Extent of disease

0 Lymphocytosis of bone marrow (>40 %) and

blood ( > 5000/ml)

I Stage 0 + lymphadenopathy

II Stage 0 or I + splenomegaly and/or

hepatomegaly

Stage 0 or I or II + anemia (Hb < 11.0 gr/dL)

III

Stage 0,I or II + thrombocytopenia (platelets <

IV
100,000/ml)
 CLL : management

• Indication for therapy :

– Persisten/progressive systemic symptoms
( fever, night sweats, weight loss)
– Lymphadenopathy that causes mechanical
obstruction or botthersome cosmetic deformities
– Progressive enlargement of lymph nodes, liver
or spleen
– Stage III or IV
– Immune hemolysis or immune thrombocytopenia
– Rapid lymphocytes doubling time
 CLL : management

• Alkylating agents
– Chlorambucil 0.1-0.2 mg/kg daily PO 3-6 weeks or
15-30 mg/m2 PO day 1( or divided over 4 days) every
14-21 days
– Cyclophosphamide 1-4 mg/kg PO daily for 10 days
• Nucleosides
– Fludarabine 25-30 mg/m2 IV daily for 5 days, every 4
weeks
– Cladribine 0.10 mg/kg daily, continous IV for 7 days or
0.12 mg/kg IV over 2 hours for 5 days, every 4 weeks
– Pentostatin 4 mg/m2 IV every other week
 CLL : management

• Combination chemotherapy :
– CVP : cyclophosphamide, vincristine, prednisone
– CHOP : cyclophosphamide, doxorubicin, oncovin,
prednison
– Cyclophosphamide, mitoxantrone, cytarabine,
cisplatin
• Rituximab
– Humanized monoclonal antibody anti CD20
• CAMPATH-1H
– Humanized monoclonal antibody anti CD52
 CLL : management
• Lym-1
– Murine monoclonal antibody that bonds to a major
histocompatibility class II antigen
• Stem cell transplantation : autologous/allogenic
• Radiation
– Reduction of lymph node masses that threaten vital
organ function and responded poorly to
chemotherapy
 CLL : management

• Splenectomy
– immune hemolytic anemia or thrombocytopnenia that
either fails to respond to corticosteroid or must be
treated chronically
– Hypersplenism
• Prednisone :
– Immune hemolysis or thrombocytopenia
– 60 mg PO daily
 CLL : clinical course

Stage Risk Median survival ( yr)

0 Low >10
I Intermediate 7
II Intermediate 7
III High 2
IV High <2
 CLL : clinical course

• Adverse prognostic factors :

– Stage III and IV
– Lymphocytes doubling time < 12 months
– Elevated level serum b2 microglobulin
– High serum level of soluble CD23
– Blood leukocyte > 30,000/ml
– Trysomi 12
– Expression of CD38
Chronic myelocytic leukemia
(CML)
 CML

• CML is a myeloproliferative disease

characterized by a proliferation of myeloid cells
without loss of their capacity to differentiate
• Peak incidence : fourth or fifth decades of life
• Slightly higher incidence in men
 CML : etiology

• Radiation
• Chemical and drugs
– benzene
 CML : pathogenesis
t (9;22) : Philadelphia chromosome

Protein BCR-Abl

Tyrosine kinase activity

Cell signal transduction :

- increased proliferation
- decreased apoptosis
CML : pathogenesis
 CML : clinical features

• Early : generalized weakness, malaise, weight

loss
• Enlarged spleen
• Bleeding manifestation (occasionaly) due to
quantitative and qualitative abnormalities of
platelets : petechiae, purpura, mucous
membrane bleeding
• Hypermetabolism : warm, moist skin and fever
 CML : laboratory

• Peripheral blood morphology :

– Erythrocytes : normochromic normocytic
– Leukocytes : leukocytosis, early granulocytic
cells ( all stadia, with predominant myelocytes
and metamyelocytes)
– Thrombocytes : normal or increased,
decreased in late stage
CML : peripheral blood
 CML : laboratory

• Bone marrow :
– Hypercellular with marked proliferation of all
granulocytic elements
– Increased number of eosinophils and
basophils
– Megakaryocytes are frequently prominent and
increased
– Mild fibrosis of marrow
 CML : laboratory

• Mild to moderate anemia

• Leukocytosis : 50,000-300,000/mm3
• Platelet : normal, increased (> 500,000/mm3) or
decreased
• LAP ( leukocyte alkaline phosphatase) : low
• Philadelphia chromosome :
– > 90 % patients
– Hallmark of CML
– Reciprocal translocation of Abl gen on chromosome 9
and BCR gen on chromosome 22
 CML : Clinical course

• Chronic phase :
– Mild anemia, splenomegaly, leukocytosis
• Accelerated phase
– Fever, marked leukocytosis, progresive anemia and
thrombocytopenia, increased basophil
– Resistant to treatment
• Blast crisis phase
– More severe symptoms than accelerated phase
– Lymphoblast or myeloblast
 CML : treatment

• Myelosuppressive agent :
– Busulfan : alkilating agent
6-8 mg/day
– Hydroxyurea : inhibitor of deoxynucleotide
synthesis
30 mg/kg /day
• Interferon a : 3-15 mU/day SC
• Signal transduction inhibitors : STI-571
( Imatinib mesylate) 400mg/d
CML : treatment : STI-571
 CML : treatment

• Spleen Radiation : limited role

• Splenectomy : refractory hypersplenism
• Leukopheresis
– When WBC > 300,000/mm3
– Leukostasis symptom : CNS, tinnitus,
priapism, pulmonary edema
• Bone marrow transplantation
 CML : treatment

• Blast crisis
– Lymhpoid blast crisis : standard ALL induction
treatment
– Myeloid blast crisis :
• AML treatment
• Imatinib mesylate 600 mg
 CML : prognosis

• Better than other leukemias

• Poor prognosis factors:
– Age > 50 years
– Increased splenomegaly
– Increased blast in peripheral blood
– Increased eosinophyl
– Increased basophyl ( > 3 %)
– Increased thrombocytes (> 1,500,000 /mm3)
• Survival : 3,5 - > 8 years
– Lymphoid crisis : remission 3-8 months
– Myeloid crisis : remission 2-6 months