Improved outcomes in E2A::HLF positive B-cell acute lymphoblastic leukemia by chimeric antigen receptor T cell therapy and BCL-2 inhibitor : Chinese Medical Journal

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Improved outcomes in E2A::HLF positive B-cell acute lymphoblastic leukemia by chimeric antigen receptor T cell therapy and BCL-2 inhibitor

Chen, Shumin1; Li, Ye1; Wang, Zheng1; Feng, Lin1; Jia, Yueping2; Mo, Xiaodong1; Wang, Yu1; Jiang, Qian1; Huang, Xiaojun1,3; Lai, Yueyun1

Editor(s): Guo, Lishao

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Chinese Medical Journal ():10.1097/CM9.0000000000002481, February 16, 2023. | DOI: 10.1097/CM9.0000000000002481
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To the Editor: The fusion gene E2A::HLF(TCF3::HLF) is formed by t(17;19) (q21-22;p13), which presents in <1% of B-cell acute lymphoblastic leukemia (B-ALL) and mainly occurs in older children and adolescents.[1] Such patients were often accompanied by drug resistance and early relapse, which confer an extremely poor prognosis, and even intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) cannot improve their survival.[2] A few studies suggested that chimeric antigen receptor T (CAR-T) cell therapy or BCL-2 inhibitors might benefit such patients, but the effectiveness needed to be further verified since the superiority of CAR-T cell therapy was restricted to individual case reports, and the efficacy of BCL-2 inhibitors was demonstrated only in vitro tests on cell lines.[1,3] Here, we retrospectively analyzed the clinical data of six patients with E2A::HLF-positive B-ALL to further validate the effectiveness of CAR-T cell therapy and BCL-2 inhibitor, which could be considered as salvage treatments in these poor-risk patients.

This study was approved by the Ethics Committee of Peking University People's Hospital (No. 2019 PHB125-001). Written informed consents were obtained from all participants. The follow-up deadline was December 2021.

All patients were female and diagnosed with E2A::HLF-positive B-ALL. All of them were characterized by the B lymphocyte markers CD10, CD19, and CD22 by immunophenotyping, and five carried t(17;19) (q21;p13) by cytogenetic karyotyping. Patients’ basic characteristics are presented in Table 1.

Table 1 - Clinical features of six E2A::HLF positive B-cell acute lymphoblastic leukemia cases.
Case no. Immunophenotype Karotype Response to induction chemotherapy Treatment after relapse or induction failure Outcome DFS (months) OS (months)
1 CD10, CD19, CD22, CD79a, TdT, CD58, CD38dim+, HLA-DR 46, XX, t(17;19) (q21;p13)[20] CR HSCT Died of relapse 11 13
2 CD10, CD19, CD7, CD22, CD79a, TdT, CD13, CD33, HLA-DR 46, XX, t(17;19) (q21;p13)[5]/46,idem,t(1;11) (p36;q23)[2]/48,idem, del(3) (p21), +13, +add(20) (p13)[4]/46,XX[1] CR Chemotherapy Died of relapse 5 10
3 CD10, CD19, CD33, CD38, CD22, CD123, TdT, HLA-DR 46, XX, t(17;19) (q21;p13)[9]/46,idem, add(14) (q32)[1]/46,XX[12] NR CD19-CAR-T + HSCT Alive 0 15
4 CD10, CD19, CD33, CD38, CD22, CD123, CD79a, CXCR4, TdT, HLA-DR 46, XX, t(5;22) (q14;q11),t(17;19) (q21;p13)[5]/46,XX[15] CR CD19-CAR-T Lost to follow-up 5 10
5 CD10, CD19, CD13, CD38, CD22, CD123, CXCR4, TdT, HLA-DR 46, XX, t(17;19) (q21;p13)[3]/46,XX,add(9) (p24)[1]/46,XX[5] CR HSCT + CD19 + CD22-CAR-T + second HSCT Alive 18 49
6 CD10, CD19, CD22, CD38, CD58, CD33, CD79a, TdT, HLA-DR 46, XX, inv(9) (p12q13)c[14] CR Venetoclax + CD19 + CD22-CAR-T Alive 11 18
CAR-T: Chimeric antigen receptor T; CR: Complete response; DFS: Disease-free survival; HSCT: Hematopoietic stem cell transplantation; NR: Non-response; OS: Overall survival.

Patient 1: A 23-year-old female patient received one course of cyclophosphamide, vincristine, daunorubicin, prednisone, and L-asparaginase (CODPL) chemotherapy after diagnosis and achieved complete response (CR). Then, she underwent HSCT after two cycles of consolidation chemotherapy and relapsed 5 months after transplantation.

Patient 2: A 15-year-old girl underwent one course of induction chemotherapy with vincristine, doxorubicin, L-asparaginase, and prednisone (VDLP) after diagnosis and achieved CR in a 4-week bone marrow evaluation. She received three cycles of consolidation therapy and relapsed 5 months after CR.

Patient 3: A 27-year-old female patient received one course of CODP chemotherapy after diagnosis and showed a poor response with 9% blasts on day 40. Then, she was given hypermethotrexate and cytarabine chemotherapy and showed progression with 60% blasts. Subsequently, she was treated with CD19-directed CAR-T cell therapy and achieved CR on day 16. She underwent HSCT 2 months later and maintained continuous CR. She survived for 15 months until the last follow-up.

Patient 4: An 8-year-old girl was treated with CODP induction chemotherapy after diagnosis and achieved CR on days 15 and 33. Subsequently, she underwent consolidation and maintenance chemotherapy and relapsed 7 months later. She was treated with CD19-directed CAR-T cell therapy and achieved CR. She maintained CR for 2 months and was then lost to follow-up.

Patient 5: A 12-year-old girl was treated with CODPL after diagnosis and achieved CR on day 35. Then, she underwent HSCT after three cycles of consolidation and relapsed at the 8th month post-transplantation. She was treated with CD19 CAR-T cell therapy and maintained CR for 18 months until she relapsed again. Thereafter, she successively received CD19 and CD22 targeted CAR-T cell therapy and achieved CR for the third time (CR3). She remained in CR3 for 9 months after the second CAR-T cell therapy and underwent a second HSCT. The patient survived for 49 months until the last follow-up.

Patient 6: An 8-year-old girl received a course of VDLP induction chemotherapy after diagnosis and achieved CR with a relatively higher level of flow cytometry minimal residual disease (FCM-MRD). Then she received BCL-2 inhibitor (venetoclax) treatment 1 month later. The FCM-MRD level was <1 × 10–4 and the E2A::HLF fusion gene turned negative. Thereafter, she was treated with venetoclax for 9 months until molecular recurrence occurred. Then, she successively received CD19 and CD22 targeted CAR-T cell therapy and achieved sustained molecular remission.

E2A::HLF is thought to be a poor prognostic indicator and associated with poor response to initial therapy and early relapse in B-ALL. At present, approximately 50 cases of E2A::HLF-positive B-ALL have been reported, out of which a majority showed immediate relapse even after HSCT, and the 5-year mortality rate was about 66%–100%.[4] In our six cases, five achieved CR after induction chemotherapy, but all relapsed finally even though two received HSCT. Such a high relapse rate (100%) and a very short disease-free survival (DFS) for only 8 months indicated that E2A::HLF-positive B-ALL had an extremely poor prognosis and even transplantation could not improve their survival.

CD19-specific CAR-T cell therapy is one of the most promising therapeutic approaches for relapsed or refractory (r/r) B-cell malignancies.[5] However, CAR-T cell therapy for E2A::HLF-positive B-ALL has rarely been reported. Wu et al[6] reported the first successful case in which CR was achieved via CAR-T cell therapy alone. Mouttet et al[3] discovered that CAR-T cell therapy as a bridge to transplantation could significantly improve the overall survival (OS) of such patients. In our case series, all six patients were positive for CD19 and CD22, which enabled CAR-T cell therapy to target either CD19 or CD22, with encouraging results. Three patients all achieved CR with CAR-T cell therapy regardless of primary resistance or recurrence. Of note, CAR-T cell therapy and the second HSCT extended the OS of Patient 5 to 49 months, making her the longest surviving person with TCF3::HLF to our knowledge. In summary, CAR-T cell therapy could enable patients to achieve CR and could be a viable bridging treatment for HSCT to improve the survival of TCF3::HLF-positive B-ALL patients.

Regarding the effect of the BCL-2 inhibitor, Fischer et al[1] reported that high expression of the anti-apoptotic oncoprotein BCL2 was a general trait of TCF3::HLF-positive ALL, indicating new therapeutic options such as the BCL2-specific inhibitor venetoclax for this fatal ALL subtype. A study by Frismantas et al[7] suggested that TCF3::HLF positive B-ALL patients showed a response to BCL-2 inhibitors via vitro tests on cell lines. However, Wu et al[6] first adopted conventional chemotherapy combined with venetoclax on a TCF3::HLF positive B-ALL patient but showed poor efficacy. In our cases, although Patient 6 was positive for FCM-MRD after induction therapy, she achieved molecular remission after venetoclax therapy and maintained DFS for 9 months, which suggested the efficacy of BCL-2 inhibitor in such patients. Although molecular recurrence occurred 9 months after venetoclax therapy, CAR-T cell therapy provided her a chance to acquire molecular remission again, which reinforced the superiority of CAR-T cell therapy.

In conclusion, CAR-T cell therapy and BCL-2 inhibitor treatment have been proven to be promising therapies and should be considered for E2A::HLF positive B-ALL.


1. Fischer U, Forster M, Rinaldi A, Risch T, Sungalee S, Warnatz H, et al. Genomics and drug profiling of fatal TCF3-HLF-positive acute lymphoblastic leukemia identifies recurrent mutation patterns and therapeutic options. Nat Genet 2015;47:1020–1029. doi: 10.1038/ng.3362.
2. Hirai M, Yagasaki H, Fujimura J, Inoue M, Shimozawa K, Okuma H, et al. Successful preemptive donor lymphocyte infusions from a haploidentical donor in a boy with E2A-HLF-positive ALL. Leuk Lymphoma 2018;59:746–748. doi: 101080/10428194.2017.1347927.
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6. Wu S, Lu J, Su D, Yang F, Zhang Y, Hu S. The advantage of chimeric antigen receptor T cell therapy in pediatric acute lymphoblastic leukemia with E2A-HLF fusion gene positivity: a case series. Transl Pediatr 2021;10:686–691. doi: 10.21037/tp-20-323.
7. Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, et al. Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood 2017;129:e26–e37. doi: 10.1182/blood-2016-09-738070.
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