Chromosomal abnormalities in Philadelphia chromosome‐negative metaphases appearing during imatinib mesylate therapy in patients with Philadelphia chromosome‐positive chronic myelogenous leukemia in chronic phase

Abstract

BACKGROUND Anecdotal cases of chromosomal abnormalities in Philadelphia chromosome (Ph)‐negative metaphases have been reported in patients with chronic myelogenous leukemia (CML) in the chronic phase during treatment with interferon and, more recently, with imatinib. This phenomenon is different from true clonal evolution in that the additional cytogenetic abnormality occurs in Ph‐negative cells. METHODS The authors analyzed their experience with 342 patients with CML in chronic phase treated with imatinib to investigate the frequency and significance of this event. RESULTS After a median follow‐up of 30 months (range, 16–35 months), 21 patients (6%; 95% confidence interval, 0.04, 0.09) developed 25 chromosomal abnormalities in Ph‐negative cells. Thirteen (54%) of these abnormalities were seen in 2 or more metaphases. The median time from the start of treatment with imatinib to the appearance of the abnormalities was 6 months (range, 3–22 months). The most common cytogenetic abnormality detected was trisomy 8 (33%). Twenty of 21 patients (95%) achieved a major (Ph < 35%) cytogenetic response (complete cytogenetic response in 13–62%). After a median follow‐up of 22 months (range, 4–33 months), all 21 patients were alive, 20 of them in chronic phase and in complete hematologic response. None of the patients showed features of myelodysplasia. CONCLUSIONS Cytogenetic abnormalities occur in Ph‐negative cells in a fraction of patients with CML in chronic phase treated with imatinib. With a short follow‐up, no clear clinical consequences can be identified. Cancer 2003. © 2003 American Cancer Society.

Clonal aberrations in Philadelphia chromosome negative hematopoiesis in patients with chronic myeloid leukemia treated with imatinib or interferon alpha

“…Our findings were in contrast to the literature reporting that most patients with evidence of Ph independent clonal evolution were at complete cytogenetic remission or showed major cytogenetic response. [6][7][8] In all, 38% (6/16) of all patients demonstrated also clonal evolution with the Philadelphia translocation. A temporal coincidence of Ph þ and Ph independent clonal evolution at the onset of the chromosomal changes in Ph À cells was found in 31% (5/16).…”

“…This corresponds to the literature, reporting median intervals from 5 to 24 months. 1,7,8 From diagnosis of CML to the first occurrence of the Ph independent clonal changes, the median Interval from diagnosis of CML to the first occurrence of the Ph independent clonal changes.…”

“…Trisomy 8 and monosomy 7 were found as the most frequent abnormalities. 1,7 Reciprocal translocations were described in Philadelphia independent clonal evolution in the literature. 1,4,8 Reciprocal translocations involving 8q have not been reported so far in Philadelphia independent clonal evolution.…”

“…Genomic instability in patients with CML was suggested. 7 Further, a multistep model of the development of CML was discussed. This implicates that the Ph translocation induces CML with the contribution of other clonal changes.…”

Extramedullary BCR-ABL1-negative myeloid leukemia in a patient with chronic myeloid leukemia and synchronous cytogenetic abnormalities in Philadelphia-positive and -negative clones during imatinib therapy

“…1 The presence of clonal chromosomal abnormalities in Phnegative cells has been described occasionally in patients with CML receiving interferon-a (IFN-a), 2 and is an increasingly recognized occurrence in patients treated with imatinib and other TKIs (for example, dasatinib, nilotinib and bosutinib). 1,3 These abnormalities appear in up to 15% of patients treated with imatinib, but are frequently transient and rarely associated with adverse clinical consequences. However, some reports have associated the development of these cytogenetic abnormalities with secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).…”