Hodgkin lymphoma (HL) encompasses two subtypes: classical Hodgkin lymphoma (cHL) and nodular lymphocyte predominant (NLPHL). cHL, constituting over 90% of cases, is aggressive, while NLPHL generally exhibits a more indolent course. The predominant subtype of cHL, nodular sclerosis cHL (NSCHL), is characterized by neoplastic lacunar-type HRS cells in a background of band-forming sclerosis, often involving mediastinal adenopathy and bulky nodes.3
Combined modality therapy, integrating chemotherapy with radiation, aims to minimize radiation doses and replace them with combination chemotherapy, balancing effectiveness with reduced toxicity. Salvage high-dose combination chemotherapy followed by autologous hematopoietic stem-cell transplantation (HSCT) yields favorable long-term outcomes, potentially curing around 50% of relapsed cHL cases. Post-ABVD positivity and residual bulky disease predict disease recurrence, with involved-field radiotherapy showing efficacy in cases with residual PET-positive illness.4 Limited regressed disease with involvement of three or fewer sites and achievement of complete metabolic response after salvage chemotherapy was found to be predictive of a more favorable prognosis.5
PULSAR (personalized ultrafractionated stereotactic adaptive radiotherapy) offers precise, adaptive radiotherapy administered at longer intervals, reducing toxicity. It can be combined with chemotherapy, immunotherapy, and surgery, providing 'precision radiotherapy' based on tumor characteristics and response to radiation dose. In two patients with recurrent nodular Hodgkin's lymphoma, significant tumor shrinkage was observed, demonstrating the necessity of combining PULSAR with adaptive radiotherapy. Additionally, long intervals between treatments minimize toxicity, particularly suitable for elderly patients or those with large tumors and p The additive effect of α-PD-L1 treatment and pulsed radiation every ten days is mediated by CD8 + T cells. Notably, PULSAR treatment induced tumor rejection upon re-challenge, indicating adaptive immune memory. Studies suggest that daily radiation may hinder immune response, emphasizing the importance of optimal timing and dosage in immunotherapy effectiveness.6 In line with our findings, which demonstrate that daily radiation scheduling does not improve when combined with immune checkpoint blockade, Filatenkov et al. showed that tumor growth after ablative radiotherapy is accelerated by subsequent 3Gy doses given daily, leading to decreased survival. 7 They used similar pre-clinical models and further demonstrated mechanistically that CD8 + T cell infiltration into tumors is hindered after repeated 3Gy daily doses, an essential predictor of immunotherapy response in humans.
In vivo studies demonstrate increased PD-L1 expression after radiotherapy, correlating with dose. Checkpoint inhibition avoids traditional cytotoxic therapy toxicities but carries autoimmune side effect risks. PULSAR-treated tumor-free mice reject re-challenged tumors, indicating adaptive immune response. Optimal radiation timing and dosage enhance immunotherapy efficacy, suggesting the potential of PULSAR in immune stimulation.8 Combining PULSAR with α-PD-L1 in an immune-activated, drug-resistant mouse model shows safety and efficacy. PULSAR, administered every ten days, improves α-PD-L1 drug efficacy compared to more frequent radiation. The mainstream radiotherapy schedule does not align well with immune drugs, advocating for PULSAR adoption to optimize PD-1 drug efficacy.9,10 Combining PULSAR with α-PD-L1 in an immune-activated, drug-resistant mouse model shows safety and efficacy. PULSAR, administered every ten days, improves α-PD-L1 drug efficacy compared to more frequent radiation. The mainstream radiotherapy schedule does not align well with immune drugs, advocating for PULSAR adoption to optimize PD-1 drug efficacy.
Decitabine, a DNA methyltransferase inhibitor, synergizes with PD-1 monoclonal antibodies, showing promise as a second-line treatment for relapsed Hodgkin's lymphoma. A randomized phase II study combining anti-PD-1 with decitabine for relapsed/refractory Hodgkin lymphoma demonstrated improved clinical outcomes. In heavily pre-treated cHL patients, Nivolumab, a PD-1 antibody, achieved a high objective response rate of 87%, including 17% complete remissions, with durable responses (86% progression-free survival at 24 weeks).11
Inflammatory markers, such as the erythrocyte sedimentation rate (ESR), can be elevated at diagnosis and serve as a helpful lab marker of disease response. Similarly, leukocytosis/neutrophilia and anemia can be seen in patients with extensive disease and ported a poorer prognosis.12 CRP is recognized as a potential biomarker for assessing cancer risk and has been validated in 12 site-specific cancers 13In Patient 1 we can see a significant decrease in LDH after the first treatment cycle, and higher levels of LDH have been shown to lead to adverse outcomes in Hodgkin's lymphoma.14 (Fig. 2.2)Therefore, we can assume by CT, PET/CT with hematological indicators that in Patient 1 and Patient 2, the relapsed/refractory lymphoma was well controlled and effectively prolonged the survival of the patients.
This case aligns with PULSAR-related studies, supporting its role in promoting immunity and optimizing combination therapies. Insights into PULSAR dosage and combination with immunotherapy underscore its potential in precision tumor therapy.
Clinical trials evaluating this treatment regimen are undergoing ethical review.
We hereby declare that all subjects involved in this study have given their informed consent for the inclusion of their data and/or images in this publication. Written informed consent was obtained from all participants, and where applicable, from their legal guardians. This consent includes the publication of identifying information/images in an online open-access publication.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.