Haploidentical HSCT May Improve Survival for Pediatric HR T-ALL

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Haploidentical Hematopoietic Stem Cell Transplantation May Improve Long-Term Survival for Children with High-Risk T-Cell Acute Lymphoblastic Leukemia in First Complete Remission

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10%–15% of pediatric ALL cases and is characterized by aggressive clinical behavior and historically poor outcomes. Despite advancements in chemotherapy regimens, children with high-risk (HR) T-ALL continue to face suboptimal survival rates, with 5-year overall survival (OS) and event-free survival (EFS) often below 50%. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential strategy to reduce relapse and improve outcomes in HR patients, particularly those in first complete remission (CR1). However, the role of allo-HSCT—especially haploidentical HSCT (haplo-HSCT)—remains under investigation, with limited data available on its comparative efficacy against chemotherapy alone. This retrospective study evaluates the impact of allo-HSCT, particularly haplo-HSCT, on survival and relapse rates in pediatric HR T-ALL patients and identifies key prognostic factors influencing outcomes.

Patient Stratification and Risk Criteria

The study enrolled 74 newly diagnosed pediatric T-ALL patients aged 1–18 years between January 2012 and June 2018. Patients were stratified into three cohorts:

  1. Low-risk chemotherapy cohort (n = 16): Patients without HR features.
  2. HR chemotherapy cohort (n = 31): Patients with HR features treated with chemotherapy alone.
  3. HR transplant cohort (n = 27): HR patients undergoing allo-HSCT in CR1, with 23 receiving haplo-HSCT and 4 receiving matched sibling donor transplants.

HR criteria included:

  • Failure to achieve CR after induction therapy.
  • Minimal residual disease (MRD) ≥1×10⁻⁴ in bone marrow (BM) at 3 months post-diagnosis.
  • Age ≥10 years.
  • Re-emergent MRD during treatment.

Treatment Protocols

Chemotherapy

Patients received either the modified Berlin-Frankfurt-Muenster (BFM) protocol or the Chinese Children Leukemia Group (CCLG)-ALL 2008 protocol. Both regimens included intensive induction and consolidation phases, with risk-adjusted intensification for HR patients.

Transplantation

Allo-HSCT was performed using myeloablative conditioning regimens without total body irradiation (TBI):

  • Matched transplants: Modified busulfan-cyclophosphamide (Bu-Cy) regimen with hydroxyurea, cytarabine, Bu, cyclophosphamide, and methyl-N-(2-chloroethyl)-N-cyclohexyl-N-nitrosourea (Me-CCNU).
  • Haplo-transplants: Added cytarabine and anti-thymocyte immunoglobulin (ATG) to the Bu-Cy-Me-CCNU regimen.
    Graft-versus-host disease (GVHD) prophylaxis included methotrexate, mycophenolate mofetil, and cyclosporine A.

Key Outcomes

Survival and Relapse Rates

  • Low-risk vs. HR chemotherapy cohorts:

    • 5-year OS: 100% vs. 58.5% (P = 0.003).
    • 5-year EFS: 83.4% vs. 54.1% (P = 0.010).
    • 5-year cumulative incidence of relapse (CIR): 6.3% vs. 45.2% (P = 0.011).

  • HR chemotherapy vs. HR transplant cohorts:

    • 5-year OS: 58.5% vs. 81.0% (P = 0.084).
    • 5-year EFS: 54.1% vs. 80.1% (P = 0.041).
    • 5-year CIR: 45.2% vs. 11.6% (P = 0.006).

Prognostic Factors

Multivariate analysis identified independent risk factors:

  1. MRD re-emergence: Associated with worse OS (HR = 2.94, P = 0.021), EFS (HR = 3.64, P = 0.005), and CIR (HR = 6.06, P = 0.002).
  2. Age ≥10 years: Linked to inferior OS (HR = 5.80, P = 0.006) and EFS (HR = 3.56, P = 0.016).
  3. High baseline WBC count (≥100×10⁹/L): Predicted higher relapse risk (CIR: HR = 3.82, P = 0.003) and lower EFS (HR = 2.77, P = 0.021).
  4. Non-transplantation: Increased relapse risk (CIR: HR = 4.39, P = 0.016).

Detailed Analysis

Early Treatment Response

All patients achieved CR, but 8 (10.8%) required extended induction. Early T-cell precursor (ETP) immunophenotype was associated with delayed CR (P < 0.001). MRD negativity at 3 months was achieved in 63 patients (85.1%), while 10 (13.5%) remained MRD-positive.

Impact of Haplo-HSCT

Haplo-HSCT demonstrated robust efficacy:

  • Relapse reduction: Only 3/23 haplo-HSCT recipients relapsed, with a 5-year CIR of 11.6%.
  • Tolerability: Transplant-related mortality was low (3/27 deaths), attributed to infections and GVHD.
  • MRD control: All transplant recipients achieved MRD negativity pre-transplant, including 6 patients with prior MRD re-emergence.

Subgroup Findings

  • ETP patients: No significant survival difference vs. non-ETP, likely due to intensive therapy and transplant utilization.
  • Older age (≥10 years): Poorer outcomes linked to chemotherapy intolerance and higher relapse risk.
  • Chemotherapy regimen: No survival difference between modified BFM and CCLG-ALL 2008 protocols.

Discussion

This study underscores the critical role of allo-HSCT in mitigating relapse and improving survival for pediatric HR T-ALL. The 80.1% 5-year EFS in the HR transplant cohort surpasses historical chemotherapy benchmarks (54.1%) and aligns with prior transplant studies, such as the German ALL-BFM trials (67% 5-year DFS). Key insights include:

  1. MRD-Driven Stratification: MRD re-emergence was the strongest predictor of relapse, emphasizing the need for timely intervention with HSCT in MRD-positive cases.
  2. Haplo-HSCT Viability: The study affirms haplo-HSCT as a safe alternative for patients lacking matched donors, with outcomes comparable to matched transplants.
  3. Age and WBC Impact: Older age and hyperleukocytosis independently predicted inferior survival, reflecting biological aggressiveness and chemotherapy resistance.

Limitations and Future Directions

  • Retrospective design: Potential selection bias and non-randomized treatment allocation.
  • Small sample size: Limited power for subgroup analyses (e.g., ETP, MRD dynamics).
  • TBI-free conditioning: While effective, long-term effects require further evaluation.

Prospective multicenter trials are needed to validate these findings and optimize risk-stratified algorithms integrating MRD monitoring and haplo-HSCT.

Conclusion

Allo-HSCT, particularly haplo-HSCT, significantly reduces relapse and enhances long-term survival in pediatric HR T-ALL patients in CR1. Key prognostic factors—MRD re-emergence, age ≥10 years, and high WBC count—should guide risk-adapted therapy. These results advocate for expanded use of haplo-HSCT in resource-limited settings and underscore the importance of MRD monitoring in treatment decision-making.

doi.org/10.1097/CM9.0000000000001999

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