A Long-Term Follow-up Retrospective Study of the Clinical Efficacy of Haploidentical Hematopoietic Stem Cell Transplantation for Early T-Precursor Acute Lymphoblastic Leukemia and T-Lymphoblastic Lymphoma
Authors: Cao Xingyu , Lu Yue , Zhang Jian-Ping , Liu Deyan , Wei Zhijie , Zhao Yanli , Zhou Jiarui , Xiong Min , Sun Ruijuan , Long Jing , Lu Peihua 
Published: December 2024

Introduction
Early T-precursor acute lymphoblastic leukemia and T-lymphoblastic lymphoma (ETP-ALL/LBL) is a distinct subtype of T-ALL/LBL originating from early thymic progenitor cells (ETP). ETP-ALL/LBL patients respond poorly to conventional first-line induction chemotherapy, with limited treatment efficacy and high relapse rates. Haplo-HCT is currently one of the most effective methods to cure ETP-ALL/LBL, but long-term follow-up results and the relationship between genes and prognosis were rarely reported.
Methods
We included ETP-ALL/LBL patients who underwent their first haplo-HCT at Hebei Yanda Lu Daopei Hospital and Beijing Lu Daopei Hospital from October 2017 to February 2023. The conditioning regimen for transplantation included myeloablative conditioning based on total body irradiation with fludarabine (TBI/FLU) or cyclophosphamide (TBI/CY). Graft-versus-host disease (GVHD) prophylaxis regimen consisted of cyclosporine A (CsA), mycophenolate mofetil (MMF), short-course methotrexate (sMTX), and anti-thymocyte globulin (ATG). For third-party unrelated cord blood infusion, human leukocyte antigen (HLA) matching was ≥4/6, with a total nucleated cell (TNC) infusion count of 0.5*10^7/kg. All patients were followed up long-term after transplantation, with the cutoff date being June 30, 2024.
Results
A total of 35 patients were included, with 28 ETP-ALL and 7 ETP-LBL patients. Clinical characteristics of these ETP-ALL/LBL patients were as follows: 26 males (74.29%) and 9 females (25.71%). The median age was 16 years (range: 6-61 years). Among them, 15 patients (42.86%) were ≤14 years old, and 20 (57.14%) were &gt;14 years old. 22 patients (62.86%) were in the first complete remission (CR1), and 13 patients (37.14%) were in the second or greater complete remission (≥CR2). HLA matching showed that 22 patients (62.86%) had a 5/10 match, and 13 patients (37.14%) had a ≥6/10 match. For haploidentical grafts, median cell counts were as follows: MNC cells ,×108/kg (10.5, range: 5.75-17.49), CD34+ cells ,×106/kg (5.00, range: 3.09-11.76), CD3+ cells ,×108/kg (1.82, range: 0.93-3.69). Neutrophil engraftment occurred in all patients (100%) at a median of 15 days (range: 11-28 days), and platelet engraftment at a median of 14 days (range: 8-28 days).
As of June 30, 2024, the median follow-up time was 24 months (range: 2.3-69.7 months), with 12 deaths recorded，of which 10 deaths (28.57%) were due to transplant-related mortality (TRM)，2 patients（5.71%） developed post-transplant lymphoproliferative disorder (PTLD) and 4 patients（11.42%）developed transplant-associated thrombotic microangiopathy (TMA). The 3-year overall survival (OS) for all ETP-ALL/LBL patients was 64.75%. Incidences of grade II-IV aGVHD, 100-day CMV-viremia, and 150-day EBV-viremia were 40%, 62.86%, and 31.79%, respectively. The 3-year OS was significantly better for ETP-ALL group compared to ETP-LBL group (73.8% vs. 28.6%, p = 0.011), and for pediatric patients (≤14 years) compared to adults (&gt;14 years) (85.71% vs. 49.65%, p = 0.039). Patients in CR1 before transplantation had a significantly better 3-year OS than those in ≥CR2 (76.71% vs. 43.96%, p = 0.047).
Genetic analysis revealed that only 3 (8.57%) patients had no detected gene mutations. The main mutated genes included NOTCH1 (71.88%), JAK3 (28.13%), PHF6 (28.13%), RUNX1 (18.75%), FBXW7 (12.5%), FLT3 (12.5%), and NRAS (12.5%). The percentage of patients with multiple gene mutations was 88.57%. Mutations in NOTCH1 and JAK3 might associated with poorer 3-year OS. ETP-ALL/LBL patients with NOTCH1 mutations had a 3-year OS of only 58.74% compared to 76.93% for patients without NOTCH1 mutations (p = 0.46). The 3-year OS was 44.44% in patients with JAK3 mutations and 71.94% in patients without JAK3 mutations, showing no significant difference (p = 0.12).
Conclusion
Haplo-HCT significantly improves long-term survival rates for ETP-ALL rather than ETP-LBL patients, particularly in pediatric patients and those in CR1 before transplantation. Gene mutation analysis revealed that NOTCH1 and JAK3 mutations are associated with poorer prognosis. If no sibling donors are available, we recommend ETP-ALL patients to pursue haplo-HCT as early as possible once achieving CR1. Additionally, personalized treatment plans should be developed based on the patient's genetic mutation status to optimize clinical outcomes.