INTRODUCTION Acute lymphoblastic leukemia (ALL) accounts for approximately 20% to 30% of adult acute leukemia cases1 and mainly originates from B- or T-lineage lymphoid progenitor cells. Among them, Ph (Philadelphia chromosome)–positive ALL is a common subtype of B-cell ALL (B-ALL). The Ph chromosome is generated by the reciprocal translocation of t(9;22)(q34;q11), which translocates the proto-oncogene ABL1 on the long arm of chromosome 9(9q34) to the BCR gene on the long arm of chromosome 22(22q11), generating the BCR-ABL1 fusion gene. Different types of BCR-ABL1 fusion proteins may occur depending on the location of the breakpoint in the BCR gene. Among them, the e1a3 type is rare in clinical practice and has a poor prognosis. Here, we report a case of an adult patient with ALL harboring the e1a3 BCR-ABL1 fusion gene that was successfully treated in our department. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) combined with dasatinib is effective. 2. CASE REPORT A 43-year-old female was admitted to a local hospital on December 6, 2019, presenting with fatigue for 1 week and fever for 1 day. Routine blood examination showed a white blood cell count of 107.1 × 109/L, hemoglobin level of 102 g/L, and platelet count of 12 × 109/L. Peripheral blood smear morphology showed that primitive lymphocytes accounted for 28%, and immature lymphocytes accounted for 61%. Bone marrow cell morphology indicated ALL-L2. Immunophenotype analysis showed that the cells mainly expressed HLA-DR, CD10, CD19, CD22, CD34, CD58, CD123, cCD79a, and TdT, suggesting B-ALL. The BCR-ABL1 fusion gene (e1a3) was positive (Fig. 1). The BCR-ABL1 fusion gene, including the e1a3 transcript, was detected by quantitative (real-time) polymerase chain reaction. Karyotype: 46, XX, t(9;22)(q34;q11) (Fig. 2). Abdominal computed tomography showed splenomegaly. The patient was diagnosed with ALL, BCR-ABL1 fusion gene (e1a3)–positive, and classified as high risk. Subsequently, the patient received the VICLP chemotherapy regimen vincristine 1.4 mg/(m2·d) × d1, d8, d15, d22 + daunorubicin 40 mg/(m2·d) × d1–3, d15–16 + cyclophosphamide 750 mg/(m2·d) × d1, d15 + asparaginase 6000 IU/(m2·d) × d19–28 + prednisone acetate 1 mg/(kg·d) × d1–14. After chemotherapy, targeted therapy with oral dasatinib 50 mg twice daily was administered at another hospital. On January 19, 2020, bone marrow cytomorphology showed complete remission (CR), and chemotherapy with the vincristine, idarubicin, cyclophosphamide, and dexamethasone (VICP) regimen combined with dasatinib (50 mg twice daily) was administered. On March 4, 2020, bone marrow cytomorphology again showed CR, and minimal residual disease (MRD) was negative. The VP regimen combined with dasatinib 50 mg twice daily was then administered (the drug doses in the VDCP and VP regimens were consistent with those in the VDCLP regimen). On March 16, 2020, bone marrow cytomorphology showed CR, MRD was negative, and the BCR-ABL1 fusion gene (e1a3) was not detected. The CAM regimen cyclophosphamide 750 mg/(m2·d) × d1, d8 + cytarabine 100 mg/(m2·d) × d1–3, d8–10 + 6-mercaptopurine 60 mg/(m2·d) × d1–7 combined with dasatinib (50 mg twice daily) was administered. On May 10, 2020, bone marrow cytomorphology showed CR, MRD remained negative, and the BCR-ABL1 fusion gene (e1a3) was not detected. The patient was human leukocyte antigen (HLA)-haploidentical with her son and underwent haploidentical allo-HSCT on May 27, 2020. Peripheral blood stem cells combined with umbilical cord–derived mesenchymal stem cells were selected for transplantation, and the preparative regimen was a modified BuCy + antithymocyte globulin (ATG) regimen, as follows: Cytarabine (Ara-C) 4 g/m2 (d−10 to d−9), busulfan (Bu) 0.8 mg/kg q6h (d−8 to d−6), cyclophosphamide (Cy) 1.8 g/m2 (d−4 to d−3), pimustine 250 mg/m2 (d−5), and ATG 2.5 mg/kg (d−5 to d−2). After transplantation, the hemogram normalized, and the patient was predicted to be at high risk of graft-versus-host disease (GVHD) (high elafin levels, indicating an increased risk of cutaneous GVHD). GVHD prophylaxis included cyclosporine, mycophenolate mofetil, and methotrexate. Although initial assessments indicated that this patient was at high risk of GVHD, the patient did not experience any clinical signs of acute GVHD during the post-transplant hospitalization or during subsequent follow-up. On day 28 post-transplantation, bone marrow cytomorphology showed CR; MRD was negative; BCR-ABL1 fusion gene (e1a3) quantification was not detected; and complete donor chimerism was maintained. On July 6, bone marrow cytomorphology showed CR; MRD was negative; BCR-ABL1 fusion gene (e1a3) quantification was not detected; complete donor chimerism was maintained; GVHD risk was predicted to be high; and cytomegalovirus (CMV) DNA quantification was 7.79 × 102 copies/mL. Antiviral therapy was administered immediately, and targeted therapy with dasatinib (50 mg once daily) was initiated simultaneously. Two weeks later, the patient’s condition improved, and she was discharged. Subsequently, follow-up at another hospital revealed that the primary disease remained stable. Dasatinib was discontinued after 2 years of maintenance treatment with dasatinib (50 mg once daily); the patient’s condition has remained stable to date.Figure 1.: Detection of recombination sites of BCR/ABL1 fusion gene.Figure 2.: Karyotype: 46, XX, t(9;22)(q34;q11).3. DISCUSSION The Ph chromosome formed by the reciprocal translocation of t(9;22)(q34;q11) is the basis for the diagnosis of chronic myeloid leukemia (CML). However, this translocation has also been observed in cases of ALL and in some cases of acute myeloid leukemia (AML). The breakpoints on chromosome 9 are located between exons 1a, 1b, and a2, while those on chromosome 22 occur within the BCR gene, which consists of 23 exons, resulting in multiple fusion genes. In general, breakpoints in the BCR gene occur between exons e12 and e16 (b1–b5), known as the major breakpoint cluster region (M-bcr), located in the central region of the gene, while rare breakpoints occur in the other 2 breakpoint cluster regions: minor bcr (m-bcr) and micro bcr (μ-bcr). The breakpoints are located between exons e1 and e2 and exons e19 and e20, respectively. To date, 3 common BCR-ABL1 fusion gene types have been reported: e1a2 (p190), e13a2/e14a2 (p210), and e19a2 (p230); other rare forms include e1a3, e13a3, and e6a2.2,3 p190 mainly occurs in ALL, p210 mainly occurs in CML, and p230 is commonly observed in chronic neutrophilic leukemia. The e1a3 transcript is produced by a translocation between exon 1 of the BCR gene on chromosome 22 and exon 3 of the ABL1 gene on chromosome 9.2 The exon 2 region of ABL1 encodes part of the Src homology (SH) 3 domain, which is absent in the e1a3 BCR-ABL1 transcript. The SH3 domain negatively regulates the kinase domain. Deletion or mutation of the SH3 domain may contribute to the invasiveness of Ph+ leukemia because it results in the loss of its inhibitory effect on kinase activity. In contrast, the SH3 domain is required for BCR-ABL1 to activate signal transducer and activator of transcription 5 (STAT5). Therefore, the absence of the SH3 domain may slow disease progression.2 Martinez-Serra et al4 found that in e1a3-positive CML, the lack of the SH3 domain is related to poor response to imatinib and rapid disease progression. However, Molica et al5 reported that e1a3-positive CML was associated with an indolent clinical course, a low white blood cell count, a prolonged untreated chronic phase, and a favorable response rate to tyrosine kinase inhibitors (TKIs). Sheets et al6 reported a patient with e1a3-positive Ph+ AML who achieved CR after 3 months of targeted TKI monotherapy, but subsequently relapsed with a T315I mutation and eventually died. Chen7 reported a patient with e1a3-positive Ph+ ALL who progressed rapidly after diagnosis and eventually died. Regarding the clinical outcomes and prognosis of patients with e1a3-positive Ph+ ALL, López-Andrade et al8 analyzed 19 cases of e1a3-positive Ph+ ALL and 1 case of Ph+ ALL in CML blast crisis. The results showed that 44% of patients were refractory or relapsed after treatment, and 55% died before the last follow-up. To date, 5 cases of e1a3-positive Ph+ ALL have been reported in China,9–11 including one described by López-Andrade et al.8 Among the other 4 patients, 1 did not receive TKI-targeted therapy and died 1 month after chemotherapy. Three patients achieved CR after receiving chemotherapy combined with TKI-targeted therapy, but 1 died of infection 6 months after onset owing to the T315I mutation. In addition, Zhou et al12 suggested that patients with CML harboring the e1a3 variant have an increased risk of relapse and/or TKI resistance and often require multimodal treatment strategies combining chemotherapy or allo-HSCT. Taken together, e1a3 BCR-ABL1 transcripts are rare in clinical practice. A few studies have evaluated their clinical outcomes and prognosis in CML, AML, or ALL. Based on previously reported cases, chemotherapy combined with TKI therapy may be more effective for such patients. Nevertheless, further studies are needed to determine how patients can achieve long-term survival. Ph+ ALL is a common type of adult B-ALL, with an incidence of 25% to 30%.7 Patients with Ph+ ALL are relatively less sensitive to chemotherapy. Before the introduction of TKIs, the prognosis of patients with Ph+ ALL was extremely poor. More recently, with the development and advancement of TKIs, the prognosis and long-term survival of patients with Ph+ ALL have substantially improved.13 Compared with imatinib, dasatinib therapy was associated with improved long-term survival, which may be related to deeper molecular response.14,15 In addition, Ma et al16 analyzed the clinical and biological characteristics, efficacy, and prognostic factors of 52 patients with Ph+ ALL. The authors identified the choice of TKI for induction therapy and subsequent allo-HSCT as crucial factors affecting overall survival. In the present case, the patient had e1a3-positive Ph+ ALL. After diagnosis, chemotherapy combined with dasatinib-targeted therapy was administered. Bone marrow examination showed sustained CR, negative MRD, and the BCR-ABL1 fusion gene (e1a3) was not detected. Following a comprehensive evaluation, allo-HSCT was performed. After transplantation, the hemogram normalized, the patient’s condition remained stable, and the therapeutic outcome was favorable. In summary, both previous clinical reports and the clinical course of this patient suggest that e1a3-positive Ph+ ALL may be sensitive to dasatinib, a second-generation TKI. For patients with e1a3-positive Ph+ ALL, dasatinib-based therapy combined with allo-HSCT may be an effective treatment strategy and may help improve long-term survival. However, owing to the small number of cases, these findings have certain limitations. In addition, given the rarity of e1a3 transcripts, when atypical BCR-ABL1 transcripts cannot be detected by conventional screening methods, fluorescence in situ hybridization or next-generation sequencing should be performed to avoid missed and incorrect diagnoses.7 ACKNOWLEDGMENTS This study was supported by the Gansu Province Innovation Base and Talent Plan (Gansu Province Leukemia Clinical Research Center)(21JR7RA015), Key research and development plan of Gansu Province (22YF7FA106), Science and Technology Program Project of Gansu Province (25JRRA1184), and Project of Hematology Medical Research Center of 940th Hospital of Joint Logistic Support Force (2021yxky078). All authors thank the patient. ETHICAL APPROVAL Not applicable. AUTHOR CONTRIBUTIONS W.L. analyzed data and wrote the manuscript. T.W. read and reviewed the final manuscript. Y.L., Q.W., and X.W. collected some clinical data.
Liu et al. (Mon,) studied this question.