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Chromosomal Abnormalities Can Occur During Imatinib Therapy in Philadelphia chromosome-negative metaphases in Patients with Chronic Myelogenous Leukaemia

Cytogenetic abnormalities are detected in Philadelphia chromosome (Ph)-negative cells in a fraction of patients with chronic myelogenous leukaemia (CML) treated with imatinib mesylate in the chronic phase of the disease, according to a recent American study.

CML is a myeloproliferative disorder characterized by a specific cytogenetic abnormality known as the Philadelphia chromosome (Ph). Disease progression can be followed by detection of additional cytogenetic abnormalities in Ph-positive cells.

Recent case reports have suggested that cytogenetic abnormalities can also occur in Ph-negative cells during interferon or imatinib therapy in CML patients. However, larger studies are needed to validate these anecdotal cases.

Jorge Medina, MD, and colleagues at the University of Texas, M. D. Anderson Cancer Center, Houston, United States, therefore evaluated the frequency and clinical significance of cytogenetic abnormalities in Ph-negative cells in 342 patients with CML treated with imatinib.

The study included patients with CML who were treated with imatinib mesylate (400-800 mg/day) in the chronic phase of the disease. Cytogenetic analysis using the G-banding technique was performed before treatment and every 3 months during treatment up to a median of 30 months.

Overall, 25 chromosomal abnormalities were detected in the Ph-negative cells of 21 patients, representing only 8% of 272 patients who achieved a cytogenetic response. The most common abnormalities found were trisomy 8 (38%), monosomy 7 (19%), deletion 20q- (14%), and monosomy 5 (9%).

Interestingly, abnormalities were also observed in 2 patients who had not received any type of previous treatment and no abnormalities were found in patients receiving higher doses of imatinib.

Abnormalities appeared at a median of 6 months after initiation imatinib treatment (range 3-22 months) and were frequently transient, as almost half were observed only once. Furthermore, 13 (54%) of these abnormalities were seen in 2 or more metaphases.

All patients showed a cytogenetic response during treatment. Specifically, 62% of patients showed a complete response and 38% showed a partial response at some point during the study. However, by final follow-up, only 48% had maintained a complete response, 33% still had a partial response and 19% had a minor response.

At a median follow up of 30 months, all patients with chromosomal abnormalities were alive and 95% were in the chronic phase and in complete haematologic response.

Grade 3 or worse myelosuppression occurred during treatment in 3 patients, specifically 2 cases of neutropenia and 1 case of thrombocytopenia. Notably, no patients developed myelodysplasia.

The authors conclude that "cytogenetic abnormalities occur in Ph-negative cells in a fraction of patients with CML in chronic phase treated with imatinib." Based on these findings, the authors recommend "close monitoring of patients with CML who receive imatinib." "The long-term significance of these abnormalities remains to be determined," they add.


Cancer 2003 Nov 1;98:9:1905-11. "Chromosomal abnormalities in Philadelphia chromosome-negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase"

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