Clonal Heterogeneity in TEL/AML1+ Acute Lymphoblastic Leukemia (ALL): A Clinical Appraisal

Introduction: In TEL/AML1+ ALL, the formation of the fusion gene is frequently followed by clonal evolution, with the acquisition of additional aberrations, some involving the TEL and AML1 genes. The resulting variant subclones often coexist at diagnosis, but the clinical significance of this heterogeneity is unclear.

Patients and Methods: The study included a group of 28 children with ALL, found TEL/AML1+ on interphase FISH. In all cases, 500 nuclei were assessed and all signal patterns indicative of a typical t(12;21) or any deviation were recorded. The patients were treated according to the BFM-95 protocol and followed-up for 5,3 to 101,10 (median 66,40) months.

Results: In 19 cases, a single clone was found. In 12 of them (Group A), the typical pattern was obtained, while in 7 (Group B) there were additional aberrations (deletion of the non-rearranged TEL in 4; fusion duplication in 1; both in 2). In the rest 9 cases (Group C), we found coexistence of two (7) or three subclones (1). Certain variations (i.e. fusion triplication or AML1 deletion) were not seen in cases with a single clone, typical or variant. Epidemiological and biological variables and outcome were comparable between the three groups. However, 8 of the 9 children in Group C had residual disease detectable by flow cytometry on D15, versus only 2 and 1 patients in Group A and B respectively (p< 0,05). One patient in Group A relapsed and subsequently died with the same signal pattern as in diagnosis. There was another relapse in Group C, but the patient entered a second remission on re-induction. Interestingly, in this latter case, involving the only patient with three subclones seen on diagnosis, all three were also present on relapse, at comparable percentages as in diagnosis.

Conclusions: Clonal heterogeneity is frequent in TEL/AML1+ ALL. It is associated with a slower clearance of the marrow on induction but not with the long-term outcome. However, this is unlikely to reflect the presence of a more resistant subclone with regard to additional aberrations of TEL and AML1 genes, since the presence of residual disease on day 15 was seen in similar frequency in patients with a typical t(12;21) and in those with a single variant clone. It is possible that patients with clonal heterogeneity may harbor other cytogenetic abnormalities involving other genes or chromosomes. Further study will be necessary to endorse this hypothesis and, perhaps, identify new pathways in the development of TEL/AML1+ ALL.