Good Prognosis of CML Patients with Clonal Cytogenetic Abnormalities in Ph-Negative Cells.

Background: Clonal cytogenetic abnormalities (CCA) have been detected in Philadelphia chromosome (Ph)-negative cells of some patients with chronic myeloid leukemia (CML) who attain a cytogenetic response to imatinib. The spectrum of abnormalities is reminiscent of that in patients with myelodysplastic syndromes (MDS), raising concerns that this may not be a benign condition. However, the prognosis of such patients has not been studied systematically.

Patients, methods, results: In a Phase II study (0110 trial, Novartis), 532 patients with CML in late chronic phase (resistant to or intolerant of interferon-alpha) were treated with an initial dose of 400 mg/day imatinib. A review of cytogenetic reports collected wthin the first 30 months of therapy identified 36 patients with CCA in Ph-negative cells (6.77%). Six of these patients (1.12%) had constitutional abnormalities. In five additional cases (0.94%) it could not be established whether the abnormalities were present in Ph-positive or Ph-negative cells. In the remainder the most frequent findings were -Y (n=11) and trisomy 8 (n=10). Chromosomes 5, 7, 10 and 20 were involved in 3 cases each. The median proportion of Ph-negative abnormal metaphases at first occurrence was 23% (range, 3–100). In 2 cases the same additional abnormality was seen in Ph-positive and Ph-negative cells, consistent with acquisition prior to Ph. All but 4 patients with abnormalities attained a major cytogenetic response (MCR), suggesting that a significant cytogenetic response is required for CCA in Ph-negative cells to become detectable. A comparison of baseline characteristics, including standard demographics, disease duration and blood and bone marrow differential counts failed to identify significant differences between MCR patients with and without CCA in Ph-negative cells. Median overall survival in MCR patients with and without CCA in Ph-negative cells was 52.2 (range, 10.4–56.6) and 52.4 (range 16.1–55.0) months (p=0.92) and median progression free survival was 50.6 (range 1.9–55.8) months and 52.0 (range 5.8–55.0) months (p=0.72). The incidence of grade 3/4 neutropenia (39.9 vs. 29.6%, p=0.22) and thrombocytopenia (17.0% vs. 14.0%, p=0.72) was similar in patients with and without CCA in Ph-negative cells. These results were identical irrespective of whether patients with constitutional abnormalities and/or the 5 unclear cases were included in the analysis. Analysis of exposure to cytotoxic drugs prior to imatinib as a potential risk factor and review of pathology reports are in progress. Thus far progression to MDS has been reported in only one patient with abnormalities of chromosomes 1+10.

Conclusions:

• No specific risk factors associated with abnormalities in Ph-negative cells were identified.

• (ii) CML patients with an MCR to imatinib who develop CCA in their Ph-negative cells have the same good prognosis as patients without such abnormalities.

• (iii) The incidence of MDS appears to be low.