A Retrospective Evaluation of Clonal Cytogenetic Abnormalities in Ph Negative Clones in Patients with CP-CML on Therapy

Cytogenetic clonal aberrations in CML are a well recognized indicator of transition to blast phase. However, it is unclear how to interpret such changes when they occur in cells not harboring a Philadelphia Chromosome (Ph-), considering that some of these changes are often seen in patients with MDS/AML. In this retrospective review of 208 cases, we sought to determine the frequency, onset, character, and general course among CML patients harboring clonal chromosomal abnormalities (ChA) in Ph- cells during treatment with tyrosine kinase inhibitors (TKI’s). In this cohort, we were able to identify 13 ChA among 11 patients (5% of initial cohort), with most cases demonstrating trisomy 8 (31%), monosomy 7 (23%), and loss/gain of chromosome Y (38%). The median number of treatments per patient was 2 (1–3), with a median followup of 77.5 months (18–196 mo) among these 11 patients. Of the 13 ChA, 9 occurred during Imatinib therapy, and 5 of these 9 resolved without a change in medication. Of the remaining 4 patients, 2 presented with ChA prior to therapy, and 2 developed ChA while on a second generation TKI (Nilotinib, Dasatinib). The ChA persisted in the patient taking Nilotinib and resolved in the Dasatinib treated patient without change in therapy. Among those with ChA prior to therapy, the ChA resolved in one after the addition of INNO-406 (a lyn-abl inhibitor), and in the other despite going untreated between interval marrow specimens (this patient later went on to receive Imatinib with no ChA over an 18 month followup). CML disease course in patients with ChA in Ph- clones does not appear to be more severe, with only one patient having gone on to receive bone marrow transplantation for accelerated phase disease, and one other not currently in cytogenetic remission. Ten patients have attained complete (6) and major (4) molecular responses. Seven patients demonstrated cytopenias at last followup. Accompanying marrow dysplasia was seen among 4 of these patients. Interestingly, cytopenias are most pronounced in those with persistence of the ChA, including one patient with 5q deletion and another with chromosome 7 deletion. In summary, while clonal cytogenetic changes in Philadelphia Chromosome positive cells are a well recognized marker of disease progression, their presence in cells lacking this translocation does not seem to reflect a similar disposition. However while cytopenias of varying severity are noted in the patients reported, there is no evidence of transformation to MDS/AML nor a more resistant disease course. Long term follow up still is needed to confirm these data.