Treatment Outcome in Children with Central Nervous System-Positive Burkitt Lymphoma Using Only Intrathecal and Systemic Chemotherapy Combined with Rituximab
Burkitt lymphoma (BL) is a highly aggressive form of non-Hodgkin lymphoma (NHL) that predominantly affects children and adolescents. It is the most common subtype of pediatric NHL, accounting for nearly 40% of cases. While the overall survival (OS) rate for BL has significantly improved with current chemotherapy regimens, reaching nearly 90%, the prognosis for patients with central nervous system (CNS) involvement remains poor. CNS-positive (CNS+) BL represents a high-risk subgroup, with approximately 25% of children and adolescents presenting with CNS disease at diagnosis. This study aimed to evaluate the demographic characteristics, treatment outcomes, and prognostic factors in children with CNS+ BL treated with a modified LMB96 regimen combined with rituximab at Beijing Children’s Hospital (BCH) in China.
Background and Significance
BL is characterized by rapid tumor growth and a high propensity for CNS involvement. The CNS+ subgroup is particularly challenging to treat due to the blood-brain barrier, which limits the penetration of systemic chemotherapy. Historically, CNS+ BL patients have had a poor prognosis, with survival rates significantly lower than those without CNS involvement. The introduction of high-dose methotrexate (HD-MTX) and intrathecal (IT) chemotherapy has improved outcomes, but the addition of rituximab, a monoclonal antibody targeting CD20 on B cells, has further enhanced survival rates.
The LMB96 regimen, developed by the French-American-British (FAB) cooperative group, has been a cornerstone in the treatment of pediatric BL. This regimen includes systemic chemotherapy, IT therapy, and, in some cases, CNS radiotherapy. However, the use of craniocerebral radiotherapy has been associated with long-term neurocognitive sequelae, prompting modifications to the regimen to eliminate radiotherapy while increasing the dosage of MTX to improve CNS penetration.
Study Design and Methods
This retrospective study analyzed 78 children diagnosed with CNS+ BL at BCH between 2007 and 2019. All patients were treated with a modified LMB96 regimen, which included systemic chemotherapy, IT therapy, and rituximab. The study aimed to evaluate the efficacy of this treatment approach and identify prognostic factors associated with survival.
Inclusion criteria required patients to be newly diagnosed with CNS+ BL and treated with the BCH-B-NHL regimen. Exclusion criteria included patients who were transferred from other hospitals after initiating treatment, those who discontinued treatment due to financial constraints, and those who died before starting chemotherapy. Clinical data, including age, sex, disease stage, CNS involvement, and treatment outcomes, were collected and analyzed.
Patient Characteristics
The study included 78 patients, with a median age of 5.7 years (range: 1–14 years). The cohort consisted of 65 boys and 13 girls, reflecting the male predominance typically observed in BL. Bone marrow invasion was present in 48.7% of patients, and CNS involvement was classified into three categories: cranial nerve palsy (CNP) in 61.5%, intracerebral mass (ICM) in 56.4%, and para-meningeal extension (PME) in 32%. Abnormal cerebrospinal fluid (CSF) morphology and immunophenotype were observed in 19.2% of patients each.
Treatment Regimen
The treatment regimen was based on the modified LMB96 protocol, which included systemic chemotherapy, IT therapy, and rituximab. The total dosage of MTX was 29 g/m², administered in combination with triple IT therapy (MTX, dexamethasone, and cytarabine) 11 times. Rituximab was administered at a dose of 375 mg/m² six times. Patients with bulky disease or high uric acid levels received urate oxidase to prevent tumor lysis syndrome.
The treatment protocol consisted of multiple phases, including COP (cyclophosphamide, vincristine, and prednisone), COPADM (cyclophosphamide, vincristine, prednisone, doxorubicin, and MTX), and CYVE (cytarabine and etoposide). The regimen was designed to achieve high-dose systemic chemotherapy while minimizing the risk of severe toxicities.
Treatment Outcomes
The median follow-up time was 34 months (range: 1–72 months). The overall response rate to treatment was 98.7%, with 59 patients achieving complete remission (CR). Five patients died of treatment-related infections, and 13 experienced disease recurrence. One patient developed a second tumor (acute myeloid leukemia) six months after treatment cessation. The 3-year OS and event-free survival (EFS) rates were 78.9% ± 4.7% and 71.4% ± 6.0%, respectively.
Prognostic Factors
Univariate analysis identified several factors associated with poor EFS, including treatment with chemotherapy alone (without rituximab), involvement of four or more organs at diagnosis, and the presence of ICM. Multivariate analysis confirmed that treatment with chemotherapy only and involvement of four or more organs were independent risk factors for EFS.
Discussion
The results of this study demonstrate that the modified LMB96 regimen combined with rituximab is highly effective in treating CNS+ BL in children. The 3-year OS and EFS rates of 78.9% and 71.4%, respectively, represent a significant improvement over historical outcomes for this high-risk subgroup. The addition of rituximab to the treatment regimen has been a key factor in improving survival rates, consistent with findings from other studies.
The study also highlights the importance of early and aggressive treatment to prevent disease progression and reduce the risk of relapse. The use of HD-MTX and IT therapy effectively targets CNS disease, while the elimination of craniocerebral radiotherapy reduces the risk of long-term neurocognitive sequelae. However, the study also identified treatment-related infections as a significant cause of mortality, underscoring the need for improved supportive care to manage toxicities and complications.
Limitations and Future Directions
While this study provides valuable insights into the treatment of CNS+ BL, it has several limitations. The retrospective design and single-center nature of the study may limit the generalizability of the findings. Additionally, the small sample size of patients treated with chemotherapy alone (without rituximab) may have influenced the statistical significance of the results.
Future research should focus on conducting large-scale, multicenter randomized controlled trials to further validate the efficacy of the modified LMB96 regimen combined with rituximab. Additionally, studies should explore strategies to reduce treatment-related complications, particularly infections, to further improve survival outcomes.
Conclusion
The modified LMB96 regimen combined with rituximab has significantly improved the treatment outcomes for children with CNS+ BL in China. The regimen effectively targets CNS disease while minimizing the risk of long-term toxicities. However, treatment-related infections remain a significant challenge, highlighting the need for improved supportive care. Continued research and collaboration are essential to further optimize treatment strategies and improve survival rates for this high-risk patient population.
doi.org/10.1097/CM9.0000000000001386
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