Chronic Myeloid Leukaemia

A balanced translocation between chromosomes 9 and 22 [t(9;22) the Philadelphia chromosome] creates a unique gene designated BCR-ABL, which codes a 210-kDa protein (p210) that functions as tyrosine kinase. The t(9;22) is not only diagnostic of CML, it is also the causative genetic event.

In a patient with CML, all cells of the hematopoietic lineage contain this translocation, proving clonality at the stem cell level and the proliferative advantage of cells with BCR-ABL gene expression. After several years of this proliferative phase (also called the chronic phase), additional genetic abnormalities lead to loss of differentiation and progression into acute leukemia (blast crisis) that is fatal within a few months.

Imatinib mesylate is an oral drug that targets and inhibits the BCR-ABL tyrosine kinase and thereby suppresses or eliminates the CML clone. 85% of patients taking imatinib achieved complete cytogenetic remission on karyotype analysis. When the dose of imatinib mesylate was increased, a significantly higher number of patients achieved a molecular complete remission with reduction in progression to blast crisis.

The majority of these patients continue to have evidence of the CML clone when investigated with sensitive techniques such as PCR, indicating that they are still at risk of relapse. Recent studies suggest approximately a 4% annual relapse rate during imatinib therapy. Patients with no detectable CML clone by PCR analysis had long-term CML-free survival.

Some patients develop re-emergence of the CML clone with resistance to imatinib mesylate due to mutations or amplifications of BCR-ABL. New targeted drugs show promise in treating patients refractory to imatinib due to these mutations. Second generation Tyrosine Kinase Inhibitors are: Nilotinib, Dasatinib, Bosutinib and MK - 0457.

Hydroxyurea and interferon with or without low-dose cytarabine can be used to normalize blood counts and control the disease manifestations in patients intolerant to imatinib mesylate.

Allogeneic stem cell transplantation can bring about long-term survival in CML. The best results are obtained in patients with HLA-identical sibling donors transplanted during early chronic phase, that is, within 1 year of diagnosis. Transplant-related mortality increases as these variables change.

Relapse after allogeneic transplantation is uncommon if transplantation is performed during chronic phase, and post-transplant relapse can be successfully treated with infusion of donor lymphocytes without any need for cytotoxic therapy. Only one third of patients are candidates for allogeneic stem cell transplantation, and because of the effectiveness of imatinib mesylate, the selection of patients and the timing of this toxic procedure require careful consideration.

Eastern Cooperative Oncology Group ( ECOG ) performance status scale:
STATUS Description
0 Asymptomatic, fully active and able to carry out all predisease performance
without restriction.

1 Symptomatic, fully ambulatory but restricted in physically strenuous activity and
able to carry out performance of a light or sedentary nature.

2 Symptomatic, ambulatory and capable of all self-care but unable to carry out any
work activities. up and about more than 50%of waking hours: in bed less than
50%of day.

3 Symptomatic, capable of only limited self-care, confined to be or chair more than
50% of waking hours, but not bed ridden.

4 Completely disabled. Cannot carrry out any self-care. Totally bedridden.