Wednesday, July 10, 2013

CHRONIC MYELOID LEUKEMIA


A clonal expansion of a hematopoietic stem cell possessing a reciprocal translocation between chromosomes 9 and 22. 

This translocation results in the head-to-tail fusion of the breakpoint cluster region (BCR) gene on chromosome 22 with the ABL gene located on chromosome 9. 

Age gp. – 30 to 60 years


Etiology
  • No evidence of cytotoxic drugs or a viral etiology. 
  • Cigarette smoking accelerated the progression to blast crisis 
  • Atomic bomb survivors had an increased incidence;  only large doses of radiation can induce CML.
Three phases
  • Chronic phase
  • Accelerated  phase
  • Blast crisis phase

Clinical Presentation


Signs and Symptoms
 
Fatigue, malaise, and weight loss or  splenic enlargement and symptoms, such as early satiety and left               upper quadrant pain or mass.
 
Granulocyte or platelet dysfunction, such as infections, thrombosis, or bleeding.
 
Severe leukocytosis or thrombosis such as vasoocclusive disease, cerebrovascular accidents, myocardial infarction, venous thrombosis, priapism, visual disturbances, and pulmonary insufficiency.

Unexplained fever, significant weight loss, increasing dose requirement of the drugs controlling the disease, bone and joint pain, bleeding, thrombosis, and infections suggest transformation into accelerated or blastic phases.


Physical Findings

Minimal to moderate splenomegaly; mild hepatomegaly
Lymphadenopathy and myeloid sarcomas are unusual except late in the course of the disease; poor prognosis


Hematologic Findings in chronic phase

Elevated white blood cell counts (WBCs), with increases in both immature and mature granulocytes, are present at diagnosis; 16,000 to 200,00/cmm
Usually less than 5% circulating blasts
Platelet counts elevated or decreased, a mild degree of normocytic normochromic anemia .

Leukocyte alkaline phosphatase is low in CML cells.
Histamine production secondary to basophila is increased in later stages, causing pruritus, diarrhea, and flushing.

Bone marrow cellularity is increased, with an increased myeloid to erythroid ratio. The marrow blast percentage is generally normal to less than 5%

Marrow or blood basophilia, eosinophilia, and monocytosis

Disease acceleration: the development of increasing degrees of anemia or blood or marrow blasts between 10 and 20%, blood or marrow basophils 20%, or platelet count less than 100,000/L.
Blast crisis: Acute leukemia, with blood or marrow blasts 20%.

Chromosomal Findings

The cytogenetic hallmark of CML, is the t(9;22)

 Recognized by the presence of a shortened chromosome 22 (22q-), designated as the Philadelphia chromosome, that arises from the reciprocal t(9;22). Some patients may have complex translocations (designated as variant translocations) involving three, four, or five chromosomes (usually including chromosomes 9 and 22).

Treatment

The goal is complete hematologic, and cytogenetic remission, cure
Complete hematologic remission, WBC less than 10,000/mL, normal blood morphology, hemoglobin and platelet counts, and disappearance of splenomegaly.
Complete cytogenetic remission, no bone marrow metaphases with t(9;22).

Rapid lowering of WBCs, reduction of symptoms,   and reversal of symptomatic splenomegaly.
Imatinib mesylate tyrosine kinase inhibitorinduces apoptosis in cells expressing Bcr/Abl.

Hydroxyurea induces rapid disease control
Busulphan, an alkylating agent  acts on early progenitor
Interferon – if all other options have failed; mechanism is unknown

Autologous SCT

Intensive leukapheresis may control the blood counts in chronic-phase CML
 leukostasis-related complications such as pulmonary failure or cerebrovascular accidents,
Splenectomy for symptomatic relief of painful splenomegaly unresponsive to imatinib or chemotherapy, or for significant anemia or thrombocytopenia associated with hypersplenism. Splenic radiation

Treatment of Blast Crisis
 Only 52% of patients treated with imatinib achieved hematologic remission (21% complete hematologic remission), and the median overall survival was 6.6 months.
 allogeneic SCT with chemotherapy

Allogeneic SCT

The Patient
The Donor
Sex mismatch has an adverse effect on transplantation, with worse outcome associated with a female donor and male recipient. This has been attributed to GVHD against the male histocompatibility Y antigen.

Post-transplantation Treatment

BCR/ABL transcript levels have served as early predictors for hematologic relapse following transplantation.
Imatinib can control CML that has recurred after allogeneic SCT.

ShareThis

Google+ Badge