MCQ MAHE 2000 Pathology Answer 06

The Correct Answer is A

Chronic Myeloid Leukemia

Pathology: a pluripotent hemopoietic stem cell becomes neoplastic because of a genetic translocation (t(9;22); the 'Philadelphia' chromosome), and replaces the normal stem cells in the marrow.

All the myeloid elements of the blood then are derived from this stem cell (erythrocytes, granulocytes, monocytes, and platelets). T

he peripheral white cell count becomes elevated, and the spleen and liver may enlarge. Eventually, further genetic changes occur in the stem cell, leading to blast transformation (ie acute leukemia). The final acute leukemia may be acute myeloid leukemia (AML), or acute lymphoblastic leukemia (ALL), reflecting the pluripotent nature of the stem cell.

The Philadelphia Chromosome: a reciprocal translocation between chromosomes 9 and 22, which fuses two genes, bcr and abl. The fusion gene (bcr-abl) produces an abnormal tyrosine kinase, which is believed to ‘drive’ myeloid proliferation. A Philadelphia chromosome may also be found in some cases of de novo AML and ALL.

Clinical features: the disease may occur at any age, but peaks between 20 and 40 years. Weight loss, night sweats, and splenomegaly are common. Gout may occur.

Diagnosis:

1. The leukocyte count is elevated, often markedly
2. Granulocytes at all stages of maturation are present in the blood, but predominantly neutrophils and myelocytes. A few blasts (<10%)>
3. The spleen is usually enlarged
4. The Philadelphia chromosome (or bcr-abl fusion transcripts) can be demonstrated in myeloid cells

Complications: in the past, all patients eventually enter some kind of ‘accelerated phase’, as their disease becomes genetically unstable. This may occur abruptly over a few days, or gradually over several weeks or months.

In 1/3 cases, the transformation is to acute lymphoblastic leukemia (ALL), and to acute myeloid leukemia in the remaining 2/3. The only known curative therapy is allogeneic stem cell transplant, but imatinib (see below) has the potential to be so.

Principles of Treatment:

1. Imatinib mesylate (Gleevec, STI571) is a specific inhibitor of the bcr-abl tyrosine kinase. It is taken orally, has few side effects, produces hematological remission in at least 90% of chronic phase patients, and complete cytogenetic responses in about 75%. The long term results are unknown. Resistance occurs, often caused by point mutations in the bcr-abl gene

2. Allogeneic transplantation from an histocompatible sibling, or from a matched unrelated donor. There are serious risks of transplant mortality and Graft Versus Host Disease. Whether to use transplant as initial therapy, or after a trial of imatinib, is controversial

3. The ‘conventional’ chemotherapy agent hydroxyurea, which controls symptoms, spleen, and leukocyte count, but produces no cures, is useful as temporary ‘holding’ therapy

Prognosis:

1. Imatinib mesylate: long term survival rates unknown, but so far (4-5 years experience) much better than IFN/cytarabine

2. Allogeneic transplantation: 50-70% cures

3. Hydroxyurea: median survival approximately 4 years

Category: MAHE 2000 MCQs