Survival implications of molecular heterogeneity in variant Philadelphia‐positive chronic myeloid leukaemia

Abstract

Summary. The BCR-ABL fusion in chronic myeloid leukaemia (CML) is generated by the Philadelphia (Ph) translocation t(9;22) or, in 10% of patients, variants thereof (vPh). Deletion encompassing the reciprocal product (ABL-BCR) from the derivative chromosome 9 [der(9)] occurs in 15% of all patients, but with greater frequency in vPh patients. Reports of physical separation of ABL-BCR in nondeleted patients, as well as evolution from classical to variant Ph, introduce further heterogeneity to the vPh subgroup and raise the possibility that such translocations may herald disease progression. Survival analyses, however, have thus far yielded contradictory results. We assessed the frequency of der(9) deletions, ABL-BCR abrogation, cytogenetic evolution and cryptic rearrangement in a large cohort of 54 patients with vPh CML. Deletions encompassing ABL-BCR were detected in 37% of patients, consistent with a model in which a greater number of chromosome breaks increases the risk of genomic loss. The components of ABL-BCR were physically separated in a further 52% of patients while fused in the remaining 11%. Evolution from classical to vPh was demonstrated in three patients. The difference in survival, as indicated by Kaplan-Meier analysis, was marked between classical and vPh patients (105 vs 60 months respectively; P ¼ 0AE0002). Importantly, this difference disappeared when patients with deletions were removed from the analysis. Our study showed that, despite the existence of several levels of genomic heterogeneity in variant Ph-positive CML, der(9) deletion status is the key prognostic factor.

Applications of Fluorescence in Situ Hybridization (FISH) for Detecting Genetic Changes in Hematological Malignancies

“…In a study including Chinese patients with CML, Philadelphia positive cases (70.4%) demonstrated typical FISH pattern; 29.6% had atypical FISH pattern with 12 different types [12]. The frequency of atypical FISH patterns is comparable to the 15% reported by Cohen et al [19] and Reid et al [20]. In our study, 8% of patients with CML had atypical FISH patterns that the atypical FISH patterns were due to variant translocation; atypical BCR/ABL fused gene rearrangements on chromosome 9 or 9q deletion of the rearranged chromosome 9; coexistence of der(9q) and der(22q) deletions.…”

Derivative chromosome 9 deletions are a significant feature of childhood Philadelphia chromosome positive acute lymphoblastic leukaemia

“…These findings, albeit in only a small number of patients, contrast with the situation in CML, in which a higher incidence of deletions was demonstrated in those with variant Ph translocations. 23 One patient among the series with a single fusion signal showed, from a combination of FISH techniques, that the BCR/ ABL fusion had arisen from insertion of part of the ABL gene into chromosome 22, with no accompanying deletion of the corresponding sequences from the der (9). A number of cryptic insertions of either BCR into ABL at 9q34, as reviewed by Primo et al, 24 or rarely ABL into BCR at 22q11, 25 have been reported in CML, with the insertions confirmed by dual fusion FISH.…”

“…[9][10][11][12]23 The poor outcome has been linked to patients with a visible deletion by FISH. Cases of Ph-positive CML have been reported, which lack expression of the ABL/BCR transcript but have no visible deletions.…”

Allogeneic stem cell transplantation reverses the poor prognosis of CML patients with deletions in derivative chromosome 9

“…6 This has been regarded as the explanation for the contradictory results obtained from survival analysis. 7 Recently, deletions in der(9) were observed in FISH deletion negative cases with quantitative PCR and we cannot exclude small deletions detectable only with PCR. 8 The lack of variant translocations in patients with deletions in our material could be a chance finding, as the expected number of such patients was only 4.…”