第一部分

早期黏膜相关淋巴组织淋巴瘤的治疗和预后：一项单中心回顾研究

研究目的：早期黏膜相关淋巴组织（Mucosa-associated Lymphoid Tissue，MALT）淋巴瘤的治疗策略多样。本研究旨在评估早期MALT淋巴瘤患者的长期生存，并探讨不同治疗方式下的疾病失败风险及复发模式。

材料与方法：本研究回顾性分析了1998年至2021年间我院诊断为I–II期MALT淋巴瘤的375例患者的临床资料。根据患者首程治疗方式，将患者分为放疗组（Radiotherapy，RT；178例）和未放疗组（197例）。通过Kaplan-Meier法评估总生存率（Overall Survival，OS）、无进展生存率（Progression-free Survival，PFS）、局部区域控制率（Local Regional Control，LRC）和无远处转移生存率（Distant Metastasis Free Survival，DMFS），使用log-rank检验比较组间生存差异。采用相对生存（Relative Survival，RS）和标准化死亡比（Standardized Mortality Ratio，SMR）矫正背景死亡率，评估治疗净生存获益。通过竞争风险分析，评估淋巴瘤相关死亡（Lymphoma-related Death，LRD）和疾病累积失败风险。通过年风险率曲线动态显示淋巴瘤失败风险的时间变化趋势。

结果：全组中位随访63个月，患者的5年OS、RS和LRD分别为94.8%、99.6%和0.8%，SMR为1.59（P = 0.002）。放疗组相比未放疗组显著改善了早期患者5年RS，为102%比97.3%（HR 0.46，95%CI 0.24–0.86；P = 0.02）。放疗组SMR与匹配的正常人群相似（1.12，95%CI 0.65-1.80；P = 0.72)。放疗组的年失败风险持续低于3.0%，而未放疗组的在6.0%以上。放疗组的5年PFS和LRC均显著优于未放疗组，分别为87.1%比62.6%（HR 0.35，95%CI 0.24–0.52；P < 0.0001）和91.6%比66.8%（HR 0.19，95%CI 0.10–0.35；P < 0.0001），但5年DMFS无显著差异（91.0%比85.5%，HR 0.73，95%CI 0.37-1.45；P = 0.37）。放疗组的5年累积失败风险和局部区域失败风险显著低于未放疗组，分别为10.0%比31.5%（HR 0.32，95%CI 0.20-0.51；P < 0.0001）和5.4%比27.0%（HR 0.20，95%CI 0.11-0.37；P < 0.0001）。

结论：早期MALT淋巴瘤患者生存预后良好，但有持续的复发风险。放疗作为首程治疗降低了早期MALT患者的复发风险，并改善了净生存，是早期MALT淋巴瘤患者首选根治性治疗。

第二部分

惰性非霍奇金淋巴瘤中等剂量大分割、低剂量放疗的疗效和安全性分析：一项多中心2期单臂临床研究

研究目的：惰性非霍奇金淋巴瘤（indolent non-Hodgkin lymphoma，iNHL）的放射治疗（Radiotherapy，RT）策略不断发展，以期在优化治疗剂量的同时最大程度减少治疗毒性。本研究旨在评估一种新型的中等剂量大分割、低剂量放疗方案（12 Gy/4次）在I–IV期iNHL患者中的疗效和安全性。

材料与方法：本项多中心、单臂、II期研究在中国的4家医院开展。入组标准包括：年龄≥18岁、新诊断或复发的I–IV期iNHL（滤泡性淋巴瘤[1–3a级]、边缘区淋巴瘤和低级别B细胞淋巴瘤）患者，且美国东部肿瘤协作组体能状态评分为0–3分。患者接受受累部位放疗，总剂量为12 Gy/4次。主要研究终点为放疗后6个月的完全缓解（Complete Response，CR）率。次要研究终点包括总缓解率（Overall Response Rate，ORR）、2年局部控制率（Local Control Rate，LCR）和无进展生存率（Progression-free Survival，PFS）、急性及晚期毒性反应以及患者报告的生活质量（Quality of Life，QOL）。所有分析均基于意向性治疗原则。患者招募已完成，随访仍在进行中。

结果：在2022年至2023年期间，中国4个中心共入组了来自71例患者的73个病灶。中位年龄为55岁（四分位距[Interquartile Range，IQR]，48–65岁），男女比例为1:1.45。其中，60例（84.5%）患者Ann Arbor分期为I-II期，53例（74.6%）患者的组织学亚型为边缘区淋巴瘤。中位随访时间为19个月（IQR，16–22月），6个月CR率和ORR率分别为94.5%（69/73个病灶，95%CI：86.6–98.5%）和100%（73/73个病灶，95%CI：95.1–100%）。仅1例患者出现野内复发。18个月的LCR和PFS分别为98.2%（95%CI，94.9–100%）和89.6%（95%CI，82.5–97.3%）。最常见的不良事件为1级淋巴细胞减少（28.2%）和恶心（19.2%）。未观察到3级及以上的非血液学不良事件。淋巴细胞绝对计数在放疗后1个月开始恢复，并于6个月恢复至放疗前水平。治疗对患者生活质量的影响较小。

结论：在iNHL患者中，12 Gy/4f的放疗方案显示出良好的疾病控制和较低的毒性反应，可能成为一种理想的放疗策略。本研究为未来开展III期随机对照临床试验提供了依据和理论基础。

Part I

Treatment outcomes in early-stage MALT lymphoma: a retrospective study at a single institution

Purpose: Patients with early-stage mucosa-associated lymphoid tissue (MALT) lymphoma exhibited a favorable prognosis after various forms of treatment. The purpose of this study is to evaluate the long-term outcome in patients with early-stage MALT lymphoma and the failure pattern between treatment modalities.

Methods and Materials: A total of 375 patients diagnosed with early-stage MALT lymphoma between 1998 and 2021 in our center were retrospectively analyzed. Primary therapy was classified as radiotherapy (RT, n = 178), and other therapies (no-RT, n = 197). Overall survival (OS), progression-free survival (PFS), local regional control (LRC), and distant metastasis-free survival (DMFS) were estimated using the Kaplan-Meier method, and compared using the log-rank test. Relative survival (RS) and standardized mortality ratio (SMR) were conducted to compare survival differences between treatment modalities by controlling for background mortality and to assess the net survival benefit of treatment. Competing risk analysis was performed to evaluate lymphoma-related death (LRD) and cumulative incidence of failure. Annual hazard rate curves were used to illustrate the dynamics of the annual hazards of lymphoma failure.

Results: With a median follow-up of 63 months, the 5-year OS, RS, and LRD were 94.8%, 99.6%, and 0.8%, respectively, with an SMR of 1.59 (P = 0.002) for the entire cohort. RT versus no-RT significantly improved 5-year RS (102% vs. 97.3%; HR 0.46, 95% CI 0.24–0.86; P = 0.02). Consistently, RT was associated with better SMR of 1.12 (95% CI 0.65-1.80; P = 0.72). The annual hazard of lymphoma failure remained below 3.0% in the RT group but exceeded 6.0% in the no-RT group. RT versus no-RT significantly improved PFS and LRC. The 5-year PFS and LRC were 87.1% and 91.6% in the RT group, respectively, compared with 62.6% (HR 0.35, 95% CI 0.24–0.52; P < 0.0001) and 66.8% (HR 0.19, 95% CI 0.10–0.35; P < 0.0001), respectively, in the no-RT group. DMFS showed no significant difference between the two groups (5-year 91.0% vs. 85.5%; HR 0.73, 95% CI 0.37–1.45; P = 0.37). RT versus no-RT also significantly decreased cumulative incidences of overall failure (5-year 10.0% vs. 31.5%; HR 0.32, 95% CI 0.20–0.51; P < 0.0001) and locoregional failure (5-year 5.4% vs. 27.0%; HR 0.20, 95% CI 0.11–0.37; P < 0.0001), respectively.

Conclusion: Patients with localized MALT lymphoma had favorable survival outcomes with a persistent risk of recurrence. RT was associated with improved RS, SMR, and PFS in early-stage MALT lymphoma. These findings suggest RT is a preferred initial treatment for patients with early-stage MALT lymphoma.

Part II

Low-dose moderate hypofractionated radiotherapy for indolent non-Hodgkin lymphoma: a multicentre, single-arm, phase 2 trial

Purpose: Radiotherapy (RT) for indolent non-Hodgkin lymphoma (iNHL) has evolved to identify the optimal curative dose with minimal toxicity. This study aimed to assess the efficacy and safety of a novel moderate hypofractionated low-dose RT regimen of 12 Gy in four fractions for patients with stage I–IV iNHLs.

Methods and Materials: In this single-arm, phase 2 study, patients were recruited at four hospitals in China. Eligibility criteria included patients aged ≥ 18 years with newly-diagnosed or relapsed stage I–IV iNHL (follicular lymphoma, marginal zone lymphoma, and low-grade lymphoma) and an Eastern Cooperative Oncology Group performance status score of 0–3. Patients underwent involved-site RT, with a total dose of 12 Gy in four fractions. The primary endpoint was the complete response (CR) rate at six months post-RT. The secondary endpoints included overall response rate (ORR), 2-year local control rate (LCR) and progression-free survival (PFS), acute and late toxicities, and patient-reported quality of life (QOL). All analyses were performed by intention to treat. Recruitment is complete, and follow-up is ongoing.

Results: Between 2022 and 2023, a total of 73 sites from 71 patients were enrolled at four centers in China. The median age was 55 years (interquartile range [IQR], 48–65 years), with a male-to-female ratio of 1:1.45. Among the patients, 60 (84.5%) had stage I-II disease, and 53 (74.6%) had marginal zone lymphoma. With a median follow-up of 19 months (IQR, 16–22 months), the 6-month CR and ORR rates were 94.5% (69 of 73 sites, 95% CI 86.6–98.5%) and 100% (73 of 73 sites, 95% CI 95.1–100%), respectively. One in-field recurrence was observed. The 18-month in-field LCR and PFS were 98.2% (95% CI 94.9–100%) and 89.6% (95% CI 82.5-97.3%), respectively. The most frequent adverse events included grade 1 lymphocytopenia (28.2%) and nausea (19.2%). No grade 3 or higher non-hematologic adverse events were reported. Lymphocyte counts began to recover one-month post-RT and returned to baseline levels in six months. Minimal impact on QOL was observed.

Conclusion: Twelve Gy in 4 fractions shows a favorable disease control with minimal toxicity in patients with iNHL, suggesting its potential as an optimal radiotherapy strategy. Our study offers evidence and rationale for the design of a future phase 3 clinical trial.