Case report: Treatment of two cases of recurrent/refractory early T-cell precursor acute lymphoblastic leukemia with venetoclax combined with the CAG regimen

Early T-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a highly aggressive subtype of T-ALL. No standard chemotherapy regimen exists for patients with recurrent/refractory (R/R) ETP-ALL; in these patients, the primary goal of salvage therapy is to achieve remission as a foundation for consolidation and intensification treatments. This study reports cases of two patients with R/R ETP-ALL who underwent salvage therapy of venetoclax combined with the CAG regimen and achieved complete remission in the bone marrow. Flow cytometry results were negative for minimal residual disease. Both patients were bridged to allogeneic hematopoietic stem cell transplantation (HSCT) and in complete remission over a 3-year follow-up period. These cases show that the use of venetoclax combined with the CAG regimen may offer patients with R/R ETP-ALL an opportunity for allogeneic HSCT.


Introduction
EarlyT-cell precursor acute lymphoblastic leukemia (ETP-ALL) is a highly aggressive subtype of T-ALL characterized by the abnormal expression of myeloid/stem cell antigens.ETP-ALL responds poorly to conventional induction chemotherapy and has a lower remission rate, higher recurrence rate, and worse prognosis than other types of T-ALL (1)(2)(3)(4)(5).Despite the availability of new targeted therapies, the remission rate in patients with recurrent/refractory (R/R) ETP-ALL remains below 18% (1,6).In this report, we present two cases of adult patients with R/R ETP-ALL who underwent salvage therapy with a combination of venetoclax and the CAG (cytarabine 10 mg/m 2 q12h d1-14 + aclarubicin 20 mg d1-4 + granulocyte colony stimulating factor (G-CSF) 200 µg/m 2 qd d1-14) regimen.The regimen was well-tolerated and the patients were bridged to allogeneic 10.3389/fmed.2024.1358161peripheral blood hematopoietic stem cell transplantation (HSCT).The patients were considered cured after 3 years of follow-up.

Discussion
ETP-ALL is a novel, high-risk variant of ALL characterized by poorer clinical outcomes and higher rates of drug resistance and recurrence than typical T-ALL; it has a 10-year cumulative incidence of remission failure or hematologic relapse of 72% compared with typical T-ALL (1,5).Although there is no significant difference in overall survival between children with ETP-ALL and those with T-ALL (86 vs. 90%) (7), the complete remission rate of adults with ETP-ALL is significantly lower than that in those with non-ETP-ALL, and the median overall survival of patients with ETP-ALL is only 20 months (5).

The diagnosis of ETP-ALL is based on a combination of immunophenotypic characterization and gene expression patterns.
(1) Immunophenotype: positive for CD7, CD2, cytoplasmic CD3, and CD4; generally negative or < 75% positive for CD5; positive for one or more of the myeloid/stem cell antigens CD34, CD117, HLA-DR, CD13, CD33, CD11b, or CD65; and negative for CD1a and CD8 (8).(2) Molecular genetics: often accompanied by mutations in myeloid-associated genes such as FLT3, NRAS/KRAS, DNMT3A, IDH1, and IDH2; mutations common in T-ALL such as in NOTCH1 and CDKN1/2 are rare (9,10).ETP-ALL is often misdiagnosed owing to the atypical clinical presentation, difficulty in cytologic diagnosis, and insufficient knowledge of flow cytometric and molecular genetic features.Case 1 was initially diagnosed with T-ALL but conventional standard VDCP and hyper-CVAD AB regimens were ineffective.The bone marrow was re-examined and immunophenotyping by flow cytometry revealed obvious myeloid and stem cell markers, including CD13, CD33, CD34, CD7, and CYCD3.T cell markers were positive for CD7 and CyCD3 but negative for CD5, CD4, CD8, and CD1a.When combined with next-generation sequencing results, which revealed multiple myeloid tumor-associated mutations, the final diagnosis was revised to R/R ETP-ALL.
ETP-ALL is often misdiagnosed owing to a lack of awareness of ETP-ALL among clinicians.In such patients, conventional combination chemotherapy is ineffective or effective but prone to recurrence and refractory disease, leading to the early emergence of R/R ETP-ALL at the time of clinical treatment.Case 1 did not achieve remission after chemotherapy with the standard VDCP and hyper-CVAD A/B regimens.Case 2 achieved remission with a conventional chemotherapy regimen for ALL but developed recurrence twice.No standard chemotherapy regimen exists for R/R ETP-ALL; thus, researchers have investigated novel treatment approaches.ETP-ALL has been hypothesized to have a gene expression profile similar to that of hematopoietic stem cells and bone marrow progenitors owing to its arrest at an early stage of T-cell differentiation and myeloid differentiation potential, with high expression of genes associated with self-renewal, including LMO2, LYL1, and HHEX, as well as anti-apoptotic BCL-2 (11).Other studies have demonstrated better response with acute myeloid leukemia (AML)-type regimens, such as conventional doses of cytarabine plus 6-mercaptopurine and cyclophosphamide (12,13).These regimens have shown better response rates than ALL-type regimens; however, the results are still deemed unsatisfactory.In Case 2, ETP-ALL similarly progressed to R/R ETP-ALL without satisfactory results following treatment with the CAG regimen.Thus, the treatment of R/R ETP-ALL has proven challenging to clinicians.
Anti-apoptotic BCL-2 family proteins mediate clonal selection and survival, advantage with important roles in lymphocytes.BCL-2 protein expression is higher in ETP-ALL than in non-ETP-ALL.Venetoclax, when administered alone, alters the proliferation of human T-ALL cell lines and primary cells, particularly those with an ETP phenotype (14,15).A strong synergistic effect between venetoclax and cytarabine has also been reported (15,16).Therefore, we explored the use of venetoclax in conjunction with the CAG regimen for the treatment of R/R ETP-ALL.Complete remission was achieved in both patients with the venetoclax + CAG regimen with safe and manageable adverse effects, and ultimately, long-term survival in conjunction with allogeneic HSCT.
In conclusion, two individuals with R/R ETP-ALL successfully went into remission using venetoclax plus the CAG regimen, which may represent a novel and effective option for the treatment of patients with R/R ETP-ALL. 10.3389/fmed.2024.1358161

FIGURE 1 (
FIGURE 1 (A) Immunophenotype of Case 1 from bone marrow flow cytometry.(B) Chemotherapy regimen and therapeutic outcome of Case 1.

FIGURE 2 (
FIGURE 2 (A) Immunophenotype of Case 2 from bone marrow flow cytometry.(B) Chemotherapy regimen and therapeutic outcome of Case 2.