Concurrent BCR‐ABL1 and core binding factor beta rearrangement in de novo acute myeloid leukemia: A case report and review of literature

Abstract A distinct subset of acute myeloid leukemia (AML) is characterized by the presence of the Philadelphia chromosome (Ph+), due to reciprocal translocation t(9;22)(q34;q11.2). This chromosomal rearrangement leads to the fusion of the breakpoint cluster region (BCR) gene on chromosome 22 with the ABL1 gene on chromosome 9, generating the BCR::ABL1 fusion gene. The Ph+ AML subtype is associated with poor prognosis and resistance to conventional chemotherapy. Beyond the well‐established BCR::ABL1 fusion, recent studies have shed light on additional genetic abnormalities in Ph+ AML, including associations with rearrangements involving core binding factor beta (CBFB). We describe a case of de novo AML with concurrent BCR::ABL1 and CBFB::MYH11 rearrangements.


INTRODUCTION
The Philadelphia chromosome (Ph) is the product of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11.2).This rearrangement brings together the BCR gene on chromosome 22 and the ABL1 gene on chromosome 9, resulting in the formation of the BCR::ABL1 fusion gene.The BCR::ABL1 fusion protein, a constitutively active tyrosine kinase, drives the dysregulated proliferation and impaired differentiation of myeloid cells.The BCR::ABL1 fusion gene is known for its association with chronic myelogenous leukemia (CML) [1] but has also recently become its own entity in de novo acute myeloid leukemia (AML) [2].
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DISCUSSION
Ph+ AML is rare, ranging from 0.5% to 3%, and is associated with poor prognosis and resistance to standard AML therapies [2,9,10].
Based on our literature search, less than 30 cases have been reported regarding concurrent BCR-ABL1 and CBFB-MYH11 rearrangements in leukemia (Table 1).The majority of cases are in the CML-blast phase (CML-BP), where the progression from chronic to BP is thought to be secondary to the sequential acquisition of inv(16)(p13q22) on top of a pre-existing BCR::ABL1 rearrangement [1,25].The second patient group consists of de novo AML, where genetic alterations of BCR::ABL1 and CBFB::MYH11 were discovered simultaneously [1].
Patients with antecedent history of CML with CBFB::MYH11 and BCR::ABL1 tend to carry the p210 kD fusion protein [1], whereas de novo AML carries the p190 fusion protein [1].This dichotomy has been shown by other case reports, suggesting two distinct biological processes in these patient subgroups.As demonstrated in  1).For example, 7+3 induction therapy with high-dose cytarabine for consolidation, as well as FLAG-Ida and GO regimens were employed across these cases.Imatinib as maintenance was used in 10 (38.5%) patients, of which six (66.7%) achieved CR.Dasatinib was used in four patients (15.3%), of which two (50%) had CR.This suggests that TKI therapy may be an effective adjuvant treatment in de novo AML.A few studies reported that the BCR::ABL1 fusion transcript was no longer detected after maintenance with TKIs, suggesting that TKIs may contribute to the suppression of a secondary clone [5,25].
In our case report, the patient was treated with 7+3 induction, cytarabine for consolidation, and azacytidine with dasatinib for maintenance.He did not receive GO, nor was he suitable for allo-SCT.Complete morphologic remission with hematologic response was obtained by Day 33 and complete molecular remission by Day 49.Although he achieved rapid CR on this regimen, he experienced multiple complications related to dasatinib.This case poses a number of questions, including the optimal timing, combination, and duration of TKI therapy in the context of dual rearrangement de novo AML.Further, whether GO should be used concurrently with TKIs and the impact of allo-SCT in the management of these rare cases remains uncertain.Given the small number of cases reported, it is difficult to draw conclusions on the optimal therapy for de novo AML BCR::ABL1 and CBFB::MYH11 rearrangement.However, it appears that this patient subgroup may benefit from intensive chemotherapy regimens with the addition of TKI and GO.To date, there are no guidelines on how to manage this particular subtype of AML, which underscores the need to continue reporting cases in the literature.

eJHaem. 2024; 5 :F I G U R E 1
607-615.wileyonlinelibrary.com/journal/jha2607 Cytogenetic bone marrow test at initial diagnosis, The cytogenetic bone marrow revealed an abnormal karyotype with three distinct abnormalities including a balanced reciprocal translocation between the short arm of one chromosome 1, arrow, and long arm of one chromosome 14, with breakpoints within bands 1p32 and 14q24, reciprocal translocation between long arms of chromosomes 9 and 22, arrows, with breakpoints at bands 9q34 and 22q11.2,pericentric inversion of chromosome 16, with breakpoints at bands 16p13.1 and 16q22.

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and the long arm of chromosome 14 with breakpoints at bands 1p32 and 14q24.The second was a reciprocal translocation between the long arms of chromosomes 9 and 22 with breakpoints at bands 9q34 and 22q11.2[t(9;22)].The third was recurrent pericentric inversion of chromosome 16 with breakpoints at bands 16p13.1 and 16q22.A qualitative reverse transcriptase polymerase chain reaction (RT-PCR) detected a transcript that was consistent with a BCR::ABL1 fusion gene having an e19a breakpoint, encoding a 220 kDa fusion protein product (p230).These findings were consistent with concurrent BCR::ABL1 and CBFB::MYH11 fusion gene transcripts.The patient was treated with 7+3 induction (standard dose cytarabine 100 mg/m 2 for 7 days; daunorubicin 60 mg/m 2 for 3 days).The detection of BCR::ABL1 fusion transcript prompted the initiation of the tyrosine kinase inhibitor (TKI), dasatinib (70 mg po BID), to his regimen from Day 8 onwards.Given evidence of CBFB::MYH11 fusion transcript and CD33+ myeloblasts, the use of gemtuzumab ozogamicin (GO) was offered, but the patient refused.His hospital stay was complicated by grade two mucositis and febrile neutropenia, secondary to PICC line-associated infection with enterococcus faceium bacteremia, and treated with a two-week course of vancomycin.He developed vancomycin-induced nephrotoxicity, with a peak creatinine of 325 micromol/L.He also developed facial edema and diffuse morbilliform rash, thought to be related to dasatinib, which was held on Day 22.A skin biopsy showed non-specific perivascular inflammation.The rash improved with dasatinib discontinuation, which was restarted on Day 37 with no issue.Count recovery was evident on Day 19 with hemoglobin 74 g/L, platelets 106 × 10 9 /L, and neutrophils 1.2 × 10 9 /L.A BM done on Day 33 showed morphologic remission with no detection of BCR::ABL1 or CBFB::MYH11 fusion gene transcripts via nested RT-PCR.TA B L E 1 Summary of patient clinical features across case reports of de novo acute myeloid leukemia (AML).
Summary of cytogenetics and molecular findings.
8Abbreviations: Dx, diagnosis; F, female; FU, follow up; M, male; N/A, not applicable.TA B L E 2tis, for which dasatinib was held for 7 days.A BM examination was repeated on Day 76 and demonstrated continued morphologic and cytogenetic remission.His poor performance status and comorbidities

Table 2
[28]rmediate-risk cytogenetics[28].Based on the 27 case reports to date, there appears to be heterogeneity in chemotherapy regimens for de novo AML with BCR::ABL1 and CBFB rearrangements (Table