Abstract
Early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is a distinct subtype of T-ALL/LBL, characterized by a poor response to initial chemotherapy, a high relapse rate, and an inferior outcome. The treatment options for ETP-ALL/LBL are currently limited, and there are no reported clinical trials available for ETP-ALL/LBL. From June 2018 to June 2022, we conducted a single-arm, single-center, phase 2 trial (NCT03553238) in newly diagnosed ETP-ALL/LBL (age 14–55). Patients (N = 54) received pediatric-inspired chemotherapy plus tucidinostat, which was orally administered once daily at a dosage of 10 mg from induction to consolidation therapy. The primary endpoint was 3 year event-free survival (EFS). Secondary endpoints were overall survival (OS), relapse-free survival (RFS), complete remission rate and adverse events. The composite complete remission (CRc, complete response [CR] plus complete response with incomplete blood count recovery [CRi]) rate and MRD negativity after induction therapy was 91% (49 of 54 patients) and 65% (35 of 54 patients), respectively. The MRD negativity after consolidation was achieved in 87% patients (47 of 54 patients). With a median follow-up of 39.3 months (IQR, 20.6 to 60.0), the 3 year EFS rate was 67.7% (95% CI 56.2–81.7), the 3 year OS rate was 71.5% (95% CI 60.2–84.9) and the 3 year RFS rate was 67.5% (95% CI 55.9–81.6). The most common grade 3–4 adverse events were neutropenia (94%), anemia (85%), thrombocytopenia (76%), and infection (53%). Tucidinostat plus pediatric regimen is an effective and well-tolerated regimen for new diagnosed ETP-ALL/LBL, with high CRc and MRD negativity rates, as well as encouraging survival outcomes.
Supplementary Information
The online version contains supplementary material available at 10.1186/s13045-024-01624-8.
Keywords: Early T-cell precursor lymphoblastic leukemia/lymphoma, Histone deacetylase inhibitor, Tucidinostat
To the editor:
Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) is associated with a poor response to initial chemotherapy, high relapse rate, and an inferior outcome, with 5 year event-free survival (EFS) less than 40% [1, 2]. The GRAALL-2003, DFCI-ALL, CCG-1882, and NOPHO-ALL2008 studies have reported superior survival outcomes for adults T-ALL receiving pediatric-inspired regimens [3–6]. However, the outcomes of ETP-ALL/LBL are less satisfactory, necessitating urgent innovative treatment strategies. Tucidinostat is a novel histone deacetylases inhibitors (HDACi) independently produced in China, specifically targeting HDAC1, 2, 3, and 10 [7]. The frequency of epigenetic modifier mutations is higher in ETP ALL compared to non-ETP ALL, and these mutations are associated with inferior clinical outcomes [8, 9]. Besides, tucidinostat exerts anti-ALL effects by inhibiting the NOTCH1-MYC signaling axis and inducing necroptosis in Jurkat and HUT-78 cell lines [10, 11]. Therefore, we hypothesize that tucidinostat plus pediatric-inspired chemotherapy may be a promising treatment option for ETP-ALL/LBL.
We conducted an open-label, single-arm, single-center phase 2 trial to assess the effectiveness and safety of tucidinostat plus pediatric-inspired chemotherapy as first-line treatment for ETP-ALL/LBL patients (aged 14–55). Tucidinostat is taken orally at a daily dose of 10 mg for 31 days during induction therapy. Patients then receive 9 week tucidinostat treatment courses if they undergo Consolidation Modules 1–3 followed by transplantation, or 27 week tucidinostat courses if they undergo Consolidation Modules 1–9 without transplantation. The induction chemotherapy comprises dexamethasone, vincristine, cyclophosphamide, idarubicin, pegaspargase, cytarabine and 6-mercaptopurine. The 9 week consolidation chemotherapy (Modules 1–3) includes dexamethasone and pegaspargase alternating with cytarabine, methotrexate and cyclophosphamide. The schema of pediatric-inspired chemotherapy is shown in additional file 2: Table S1. All patients are considered for allogeneic hematopoietic stem cell transplantation (allo-HSCT) following 1 cycle of consolidation therapy (Module 1–3) if a suitable donor is available. The primary endpoint was 3 year EFS. Secondary endpoints were overall survival (OS), relapse-free survival (RFS), complete remission (CR) rate and adverse events (AEs). This trial was registered on ClinicalTrials.gov with the identifier NCT03553238. The protocol is shown in additional file 1.
From June 2018 to June 2022, a total of 54 patients were enrolled and included in the efficacy and safety analyses (Fig. 1A). The baseline patient characteristics and genetic profile are shown in additional file 2: Table S2, Fig. S1. The median duration of follow-up was 39.3 months (IQR, 20.6 to 60.0). The median EFS was not reach and 3 year EFS rate was 67.7% (95% confidence interval [CI], 56.2–81.7). The 3 year OS rate was 71.5% (95% CI 60.2–84.9) and the 3 year RFS rate was 67.5% (95% CI 55.9–81.6) (Fig. 1B–D). The composite complete remission (CRc, complete response [CR] plus complete response with incomplete blood count recovery [CRi]) was achieved in 49 patients (91%) after induction and consolidation therapy (Module 1–3) (Additional file 2: Table S3, Fig. S2). Minimal residual disease (MRD) negativity was achieved in 35 patients (65%) after induction therapy, and in 47 patients (87%) after consolidation therapy (Module 1–3). The cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) rates of entire cohort were 14.3% (95% CI 0.062–0.257) and 12.5% (95% CI 0.050–0.237), respectively (Additional file 2: Fig. S3). The survival rates did not differ significantly across age groups (Additional file 2: Fig. S4). Patients achieving MRD negativity had significantly improved survival outcomes than those with MRD positivity (Additional file 2: Fig. S5). Out of 50 patients, 35 (70%) underwent all-HSCT, while the remaining 15 (30%) continued with consolidation chemotherapy (Additional file 2: Table S4). Notably, there were no significant differences in the 3 year EFS, OS and CIR rates between allo-HSCT and continued chemotherapy (Additional file 2: Fig. S6). The NRM rate was significantly higher in the transplantation group compared to the continued chemotherapy group.
Fig. 1.
Trial profile and survival outcomes for the entire cohort, A Trial profile of the study. B–D Kaplan–Meier plots showing Event-free survival (B), overall survival (C) and relapse-free survival (D) rate of all patients over time; patients at risk at each time point are shown below graph. Tick marks indicate censored data. ETP-ALL/LBL, early t-cell precursor lymphoblastic leukemia/lymphoma; CR/CRi, complete remission/complete remission with incomplete hematologic recovery; Allo-HSCT, allogeneic hematopoietic stem cell transplantation; ITT, intention-to-treat
Tucidinostat plus pediatric-inspired regimen was generally well tolerated, and the associated AEs were manageable (Table 1). In our cohort, the incidence of grade 3–4 myelosuppression, alanine transaminase levels, and gastrointestinal AEs did not increase compared to using a pediatric-inspired regimen alone [6]. The hematologic adverse events of grade ≥ 3 included neutropenia (94%), thrombocytopenia (76%) and anemia (85%). The main non-hematologic adverse events of grade ≥ 3 was infection (57%). Two patients (4%) had fatal infection-related AEs (sepsis [n = 1], pneumonia [n = 1]). Compared to other HDAC inhibitors, the incidence of gastrointestinal AEs was lower [12].
Table 1.
Summary of adverse events after treatment of tucidinostat plus pediatric chemotherapy
| Adverse events | Grade 1–2 | Grade 3 | Grade 4 | Grade 5 |
|---|---|---|---|---|
| Hematological | ||||
| Neutropenia | 1 (2%) | 4 (7%) | 47 (87%) | 0 |
| Thrombocytopenia | 7 (13%) | 13 (24%) | 28 (52%) | 0 |
| Anemia | 7 (13%) | 44 (85%) | 0 | 0 |
| Non-hematological | ||||
| Fever | 25 (46%) | 5 (9%) | 0 | 0 |
| Infections | 2 (4%) | 17 (31%) | 12 (22%) | 2 (4%) |
| ALT increased | 12 (22%) | 4 (7%) | 1 (2%) | 0 |
| AST increased | 5 (9%) | 1 (2%) | 0 | 0 |
| Hypoalbuminemia | 41 (76%) | 0 | 0 | 0 |
| Hypokalemia | 22 (41%) | 10 (19%) | 1 (2%) | 0 |
| Fatigue | 14 (26%) | 0 | 0 | 0 |
| Vomiting | 13 (24%) | 0 | 0 | 0 |
| Diarrhea | 6 (11%) | 2 (4%) | 0 | 0 |
Data are n (%). ALT alanine aminotransferase, AST Aspartate aminotransferase
In summary, this trial is the first finished clinical trial on ETP-ALL/LBL. Tucidinostat plus pediatric regimen is a promising and well-tolerated regimen for new diagnosed ETP-ALL/LBL, with high CRc and MRD negativity rates, as well as encouraging survival outcomes.
Supplementary Information
Acknowledgements
We thank the patients and their families, the medical and nursing staffs, and members of the study team involved in this trial. Hongsheng Zhou is supported by the National Natural Science Foundation of China (number 82170163 and 81970147). Li Xuan is supported by the National Key Research and Development Program (number 2022YFC2502600-5). Yang Xu is supported by the National Key Research and Development Program (number 2022YFC2502700)
Abbreviations
- ETP-ALL/LBL
Early T-cell precursor lymphoblastic leukemia/lymphoma
- T-ALL/LBL
T-cell acute lymphoblastic leukemia/lymphoma
- HDACi
Histone deacetylase inhibitor
- EFS
Event-free survival
- OS
Overall survival
- RFS
Relapse-free survival
- CRc
Composite complete remission
- CR
Complete remission
- CRi
Complete response plus complete response with incomplete blood count recovery
- MRD
Measurable residual disease
- Allo-HSCT
Allogeneic hematopoietic stem cell transplantation
- AEs
Adverse events
- ITT
Intention-to-treat
- CIR
Cumulative incidence of relapse
- NRM
Non-relapse mortality
- IQR
Interquartile range
Author contributions
ZHS and LQF designed the clinical trial. LJP, HZC, CZH, LJ, LZ and DCH wrote the manuscript, collected data, and performed statistical analysis. All authors contributed to patient registration and treatment, provided clinical data, reviewed and approved the final version of the manuscript. ZHS and LJP accessed and verified all the data in the study. ZHS had full access to all of the data in the study and took responsibility for its integrity and accuracy of analysis. All authors had final responsibility for deciding to submit for publication.
Funding
This study supported by the National Natural Science Foundation of China (number 82170163 and 81970147) and National Key Research and Development Program (number 2022YFC2502700 and 2022YFC2502600-5).
Availability of data and materials
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This study was carried out in accordance with the Declaration of Helsinki and the China Good Clinical Practice Guidelines, and was approved by the Medical Ethics Committee of Nanfang Hospital.
Consent for publication
Written informed consent was obtained from all patients or their guardians.
Data sharing
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Jieping Lin, Zicong Huang, Zihong Cai, Jia Li, Zhen Li and Chenhao Ding contributed equally to this work.
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Data Availability Statement
No datasets were generated or analysed during the current study.