Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia<b> </b>Is Separated into Two Subgroups Associated with Survival by <b><i>BCR</i></b>-<b><i>ABL</i></b> Fluorescence in situ Hybridization of Segmented Cell Nuclei: Report from a Single Institution

Abstract

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) may include the lymphoid blast crisis of chronic myeloid leukemia (CML-BC). We applied fluorescence in situ hybridization (FISH) of the BCR-ABL fusion gene to peripheral blood and/or bone marrow smears to determine whether the fusion was restricted to mononuclear cell nuclei or if segmented cell nuclei representing mature neutrophils also carried the fusion (Seg-FISH). Among 20 patients with Ph+ ALL without a prior diagnosis of CML, 9 were Seg-FISH+ and 11 were Seg-FISH-. Seg-FISH+ cases were characterized by a higher rate of p210-type BCR-ABL transcripts, higher white cell and blast counts, and a higher rate of myeloid and T-lymphoid antigen expression than Seg-FISH- cases, in addition to ‘major route' cytogenetic abnormalities associated with CML-BC. Eighteen patients were treated with tyrosine kinase inhibitors (TKIs) either alone or in combination with multiagent chemotherapy, and 7 underwent allogeneic hematopoietic stem cell transplantation. Progression-free and overall survivals were greater in the Seg-FISH+ group than in the Seg-FISH- group. These results suggest that the Seg-FISH+ group represents lymphoid CML-BC that occurs de novo, while the Seg-FISH- represents Ph+ ALL in the strict sense, and the two groups are associated with survival when treated with TKIs or TKI-combined therapy.

Multi-Lineage BCR-ABL Expression in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Associated With Improved Prognosis but No Specific Molecular Features

“…Therefore, the analysis of other cell types or different differentiation stages between uni-Ph and multi-Ph may be necessary to observe genetic phenotypes. Survival rates were significantly different between patients with uni-Ph and those with multi-Ph, consistent with a previous smallscale study (2). The better survival rate observed for patients with multi-Ph may be due to differences in the cell differentiation stage affected by TKI treatment between the two lineages, instead of specific genetic differences in leukemic cells.…”

“…In this study, we used multiple approaches to confirm the heterogeneity of adult Ph+ALL according to BCR-ABL expression lineages (1,2). BCR-ABL signals were observed outside of leukemic blast cells in 36% of patients with Ph+ALL.…”

“…To assess the expression of the BCR-ABL fusion gene outside of leukemic blast cells, we performed FISH analyses on two different specimens: peripheral blood (PB) neutrophils (PN-FISH) (12) and bone marrow clot sections (BM-FISH) (13). A Vysis LSI BCR/ABL ES Dual-Color Translocation Probe (Abbott Laboratories, Abbott Park, IL, USA) was hybridized with PB and BM samples (2,14). The denaturation of the chromosome/probe, hybridization, and washing were performed according to the manufacturer's instructions.…”

“…Cells that express BCR-ABL outside of the B-lineage compartment have been reported in a proportion of patients with Philadelphia chromosome-positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) (1)(2)(3)(4). In most cases, the fusion gene BCR-ABL, which is the genetic abnormality associated with Ph+ALL, is expressed only in B-lymphocytes; however, in some cases, BCR-ABL was also expressed in the myeloid lineage, suggesting that these cells originated from a separate differentiation stage than B-lineage cells.…”

Interphase FISH for BCR‐ABL1 rearrangement on neutrophils: A decisive tool to discriminate a lymphoid blast crisis of chronic myeloid leukemia from a de novo BCR‐ABL1 positive acute lymphoblastic leukemia

“…In our patient, we therefore performed interphase FISH analysis for BCR‐ABL1 rearrangement in blood neutrophils, which was positive allowing us to render the diagnosis of lymphoid blast crisis of CML. Consistent with our data, Kamoda et al demonstrated that, among 20 patients with BCR‐ABL1 positive ALL, detection of BCR‐ABL1 rearrangement in segmented cell nuclei was positive in 9 cases with evidence for diagnosis of lymphoid blast crisis of CML: higher rate of p210 transcript, higher white cell and blast counts, and higher rate of myeloid and T‐lymphoid antigen expression. Furthermore, Kamoda et al suggested a greater progression‐free and overall survivals in lymphoid blast crisis of CML than in de novo BCR‐ABL1 positive ALL.…”