Myeloid neoplasms with concurrent BCR‐ABL1 and CBFB rearrangements: A series of 10 cases of a clinically aggressive neoplasm

Abstract

Chronic myeloid leukemia (CML) is defined by the presence of t(9;22)(q34;q11.2)/BCR-ABL1. Additional chromosomal abnormalities confer an adverse prognosis and are particularly common in the blast phase of CML (CML-BP). CBFB rearrangement, particularly CBFB-MYH11 fusion resulting from inv(16)(p13.1q22) or t(16;16)(p13.1;q22), is an acute myeloid leukemia (AML)-defining alteration that is associated with a favorable outcome. The co-occurrence of BCR-ABL1 and CBFB rearrangement is extremely rare, and the significance of this finding remains unclear. We identified 10 patients with myeloid neoplasms harboring BCR-ABL1 and CBFB rearrangement. The study group included six men and four women with a median age of 51 years (range, 20–71 years). The sequence of molecular alterations could be determined in nine cases: BCR-ABL1 preceded CBFB rearrangement in seven, CBFB rearrangement preceded BCR-ABL1 in one, and both alterations were discovered simultaneously in one patient. BCR-ABL1 encoded for p210 kD in all cases in which BCR-ABL1 preceded CBFB rearrangement; a p190 kD was identified in the other three cases. Two patients were treated with the FLAG-IDA regimen (fludarabine, cytarabine, idarubicin, and G-CSF) and tyrosine kinase inhibitors (TKI); seven with other cytarabine-based regimens and TKIs, and one with ponatinib alone. At last follow up (median, 16 months; range 2–85), 7 of 10 patients had died. The co-existence of BCR-ABL1 and CBFB rearrangement is associated with poor outcome and a clinical course similar to that of CML-BP, and unlike de novo AML with CBFB rearrangement, suggesting that high-intensity chemotherapy with TKI should be considered in these patients.

BCR-ABL + acute myeloid leukemia: are we always dealing with a high-risk disease?

“…Regarding the outcome of this favorable subgroup of patients with BCR-ABL 1 AML, it is surprising that many of these patients were long-term survivors, although they had been treated with chemotherapy 6 TKI alone (without allogeneic stem cell transplantation). 5,[8][9][10] These data clearly suggest that the presence of BCR-ABL did not alter the overall favorable outcome in these subgroups ( In this patient cohort, which was in part recently published, 13 a 2-year overall survival of 34% was observed. Interestingly, the survival did not substantially differ between patients achieving a CR before HSCT and patients who did not (34.7% vs 33.5%; Figure 1).…”

Mutation accumulation in cancer genes relates to nonoptimal outcome in chronic myeloid leukemia

“…This was in support with a finding suggesting a role for hybrid genes in CML progression. 13 Among the hybrid genes that we identified were known leukemiaassociated hybrids such as CBFB-MYH11, which is associated with the AML subtype M4Eo, and indicates aggressive outcome in AP/BP, 52 and RUNX1-DYRK1A, which has been linked with ALL pathogenesis. 53 Other potentially oncogenic hybrids included DSCC1-TAF2 identified in breast cancer and RSL24D1-RAB27A detected in lung adenocarcinoma.…”

Secondary Philadelphia chromosome acquired during therapy of acute leukemia and myelodysplastic syndrome

“…Adding tyrosine kinase inhibitors to the therapeutic regimens has significantly altered the outcome of patients with chronic myeloid leukemia [69,70] and Philadelphia chromosome-positive acute lymphoblastic leukemia [71,72], and the efficacy has also been shown in Philadelphia chromosome-positive de novo acute myeloid leukemia [19]. It is worth mentioning that tyrosine kinase inhibitors are effective in rare cases of myelodysplastic syndrome with the Philadelphia chromosome [73] and rare cases with concurrent BCR-ABL1 and CBFB rearrangements [31,74,75]. However, the effect of tyrosine kinase inhibitors along with or in place of chemotherapy in patients with late-acquired Philadelphia chromosome in relapsed or refractory disease is not well understood.…”