Patterns of Clonal Evolution in Ph’-Positive Chronic Myelogenous Leukemia (CML) during Chronic Phase: Overall Incidence, Type, Multiplicity, Development Time, Effect on Subsequent Genetic Instability, Sokal Risk, Type of bcr/abl Transcript and Hematological Evolution.
Authors: Luzi Debora , Falchi Lorenzo , Emili Rita , Angeletti Ilaria , Prontera Paolo , Venti Giovanna , Bassetti Alessandra , Gubbiotti Marta , Capparella Vincenzo , Gentileschi Erminia , Donti Emilio , Liberati Anna Marina 
Published: April 2020

Fifty-two kariotypic abnormalities additional to Philadelphia chromosome (Ph’) were documented at the time of diagnosis or during the course of the disease in 114 CML patients. Five were evaluated only once at the time of diagnosis, while 109 were repeatedly studied overtime during a median period of 138 (1–275)months. A clonal evolution was already present at diagnosis (early clonal evolution) in 12, while in 23 patients, it was documented in the course of the disease (late clonal evolution). Simultaneous appearence of multiple chromosome abnormalities (4/12 and 4/23) and a tendency to acquire further alterations (5/12 and 2/23, respectively) were associate with both early and late secondary clones. Partial or complete chromosome losses (-1, -6, 6q-, 7p-, 11q-, 12p-, -14, -16, -17,-18, -21) other than -Y (11 events), + 8 (9) and loss of Y chromosome (8) were the most commonly cytogenetic abnormalities, irrespective of the time of their occurrence. Translocations other than Ph’ (5 events), complex Ph’ translocations (5), duplication of Ph’ (5), single iso(Ph’) (4), duplication of iso(Ph’) (1) or iso17q (2) were found with a decreasing frequency. The type of kariotypic alteration varied with the time of onset. In fact, partial or complete chromosome monosomies and duplication of iso(Ph’) never represented early, but only late events. Duplication of Ph’ was a late (4/5) rather than an early event (1/5). Similarly, the presence of the iso(Ph’) was documented either in early or late clonal evolution in 1 and 3 instances respectively. Furthermore, +8 developed several months after diagnosis in all, but 2 cases. Complex Ph’ translocations or loss of Y chromosome do not correlate with any specific phase of the leukemic course. Cytogenetic abnormalities neither correlated with Sokal risk nor with the type of break-points (b3a2,b2a2) documented at diagnosis. However all 3 clones bearing p230 chimeric protein showed early cytogenetic evolution. Secondary clones seem to have different impact on disease history. The occurrence of partial or complete deletions, the iso17q and the late, but not early, loss of Y chromosome were all predictive of a rapid disease progression. Early secondary clones with additional translocations had no effect on the chronic behaviour of the disease, while such clones were associated with a rapid progression (2/3) to blastic phase when they occurred during the course of disease. The presence of +8 as the sole cytogenetic abnormality and complex translocations, irrespective of the time of their onset, did not correlate with leukemia evolution. Finally,simple Ph’ duplication of or single and double iso(Ph’), when not associated with other cytogenetic abnormalities, did not correlate with an aggressive course, even if it can be assumed that these cytogenetic events are responsible for an increased concentration of the p210 oncoprotein. In conclusion, regardless of whether bcr/abl has a direct or an indirect role in promoting genomic instability, in our cohort of CML patients additional non random chromosomal abnormalities frequently characterize both early and late phase of the disease and some of them may represent crucial steps in development and progression of leukemia.