Relapsed/refractory classical Hodgkin lymphoma treated with pulsed Boom-Boom radiotherapy combined with a PD-1 inhibitor and decitabine: Two case reports

Relapsed/refractory classical Hodgkin lymphoma treated with pulsed Boom-Boom radiotherapy combined with a PD-1 inhibitor and decitabine: Two case reports | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Relapsed/refractory classical Hodgkin lymphoma treated with pulsed Boom-Boom radiotherapy combined with a PD-1 inhibitor and decitabine: Two case reports Chen Wang, Zhuang Xue, Benkui Zou, Pengyue Shi, Jinbo Yue This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4636906/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Hodgkin lymphoma (HL), characterized by cancerous Reed-Sternberg cells within an inflammatory milieu, poses challenges in relapsed or refractory cases. Current standard treatments, including salvage chemotherapy and autologous stem cell transplantation (ASCT), have limitations in achieving long-term remission. Herein, we present two cases of nodular sclerosing relapsed/refractory Hodgkin's lymphoma treated with personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) in combination with a PD-1 inhibitor and Decitabine. Patients underwent PULSAR (2Gy/dose x 2f D1-2 q3w) for recurrent lesions along with PD-1 monoclonal antibody (200mg D0 q3w) and Decitabine (10mg D1-5 q3w) for six cycles. Both patients achieved complete remission (CR) post-treatment, enabling subsequent ASCT and PD-1 maintenance therapy. Follow-up revealed prolonged survival without recurrence. PULSAR, by delivering radiation pulses at longer intervals, allows for tumor adaptation and immune response, potentially enhancing treatment efficacy and minimizing toxicity. Combined with immunotherapy and Decitabine, PULSAR shows promise in managing relapsed/refractory HL, warranting further investigation through clinical trials. This approach signifies a paradigm shift towards precision tumor therapy and immunomodulation in HL management. Figures Figure 1 Figure 2 Figure 3 Figure 4 1 Introduction Hodgkin lymphoma (HL) is a unique hematopoietic cancer characterized by Reed-Sternberg cells. Most commonly diagnosed in the 20–34 age group, it can occur across all ages. Relapse signifies the disease's return after remission, while refractory refers to treatment resistance. Secondary therapies offer remission and potential cure for relapsed or refractory cases, affecting 10–30% and 5–10% of patients, respectively. treatment options depend on timing, age, health, and prior therapies. Standard secondary treatment often involves combination therapy and stem cell transplantation. Despite efforts, around 50% of patients do not achieve cure with traditional salvage chemotherapy and transplantation. 1 Research aims to improve complete response rates pre-transplantation with novel agents. Involved site radiation therapy (ISRT) targets affected and adjacent lymph nodes. Personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) delivers radiation in pulses, offering potential benefits like tumor response to treatment changes, immune system activation, and integration with other interventions. 2 Traditionally, relapsed HL is treated with salvage chemotherapy and autologous stem cell transplant (ASCT). However, some patients may not be eligible or respond poorly to this approach. This article discusses two cases of nodular sclerosing relapsed/refractory HL treated with pulsed Boom-Boom radiotherapy, a PD-1 inhibitor, and Decitabine. This combination aims to achieve complete response for ASCT, extending survival and offering an effective treatment approach for relapsed/refractory HL. 2 Method and materials Two patients with recurrent Hodgkin's lymphoma admitted to our department were retrospectively analyzed; both patients had advanced relapsed/refractory Hodgkin's lymphoma (nodular sclerosis type). Case 1 was found to have an abdominal mass on consultation for lower limb numbness, and case 2 was found on regular review imaging follow-up, both with a PET-CT Deauville score of 5 confirming the diagnosis of recurrent Hodgkin's lymphoma. Pulsed (PULSAR) Boom-Boom radiotherapy (2Gy/dose x 2f D1-2 q3w) x 6 times was administered to the recurrent lesions in combination with a DP regimen: PD-1 monoclonal antibody (200mg D0 q3w) decitabine (10mg D1-5 q3w), one cycle of treatment every 21 days, and six processes of treatment were applied(Figure 1 ). Assessed at the end of treatment, two cases were in complete remission (CR), had undergone autologous stem cell transplantation, and then entered PD-1 maintenance therapy. Now, the two patients have been treated with good results. 3 Result 3.1 Presentation of Case #1 Patient 1 is female and 35 years old. She was admitted to the hospital for "Hodgkin's lymphoma diagnosed for eight years, recurrence after radiotherapy." On February 8, 2014, paroxysmal cough, CT showed a middle and upper mediastinal space-occupying lesion, which was consistent with the CT manifestation of the tumor and was considered to be lymphoma, with a small amount of effusion in the bilateral thoracic cavity and pericardium. Lymph node biopsy pathology: (right supraclavicular) Consider classic Hodgkin's lymphoma (nodular sclerosis type). Eight cycles of ABVD regimen, PET-CT efficacy evaluation was PR on October 18, 2014. 32.4Gy/18f of chest radiation and 40Gy of GTV were performed on October 23, 2014, and the condition improved. 2022 was admitted to the hospital on April 6, 2022, for "numbness of the lower limbs." PET-CT was shown: Clinical diagnosis of Hodgkin's lymphoma after comprehensive treatment (Deauville score: 5), abdominal cavity, retroperitoneal multiple abnormal hypermetabolic occupations, considered to be lymphoma recurrence. Retroperitoneal lymph node aspiration biopsy: Consistent with classic Hodgkin's lymphoma, predisposed to nodular sclerosis type. On May 12, 2022, PD-1 + decitabine was given with boom-boom radiotherapy to the recurrent lesion (2Gy x 2 sessions) for six treatment cycles. Two cycles later on July 7, 2022.4 Repeat PET-CT: in conjunction with the clinic, after treatment of the lymphoma recurrence, mediastinal soft tissue shadows without hypermetabolism were seen; retroperitoneal soft tissue mass and small lymph nodes with mild metabolism ( Deauville score of 3. The patient was hospitalized on August 1, 2022, due to novel coronavirus pneumonia and was discharged after four days of treatment with alleviated symptoms.4 cycles later, PET-CT on August 29, 2022: combined with clinical findings, after treatment for lymphoma relapse, mediastinal soft tissue shadow, no hypermetabolism seen; retroperitoneal soft tissue mass and small lymph nodes with mild metabolism of patchy pattern (no significant change from 2022-07-04 PET). 6 cycles later, PET-CT on October 11, 2022: In conjunction with clinical, after treatment for lymphoma relapse, mediastinal soft tissue shadow, no hypermetabolism seen; retroperitoneal soft tissue mass and small lymph nodes with patchy mild metabolism (no significant change from 2022-08-29 PET). On October 10, 2022, in conjunction with PET-CT, CR status was considered, and autologous hematopoietic stem cell transplantation was given. On 2022-10-25, autologous hematopoietic stem cell transplantation was performed. Regular PD1 immuno-maintenance therapy was performed after that. In April 2023, radiofrequency ablation of arrhythmia was performed. Patient 1 was last followed up on October 4, 2023, and there were no signs of recurrence in the patient's physical condition, hematological parameters, or imaging. 3.2 Presentation of Case #2 Patient 2, female, 31 years old, presented with the following complaint: Hodgkin's lymphoma, diagnosed nine years ago, relapsed after second-line treatment. Current medical history: 2013-4-2, "found left neck mass," left neck mass resection, pathology: (left supraclavicular) classic Hodgkin's lymphoma, nodular sclerosis type. 2013-4-5, admitted to our hospital, PET-CT: lymphoma bilateral lower neck, double clavicular region, mediastinum, internal breast area multiple lymph node involvement, proper femoral neck involvement with FDG hypermetabolism. Femoral neck involvement with FDG hypermetabolism. After eight cycles of chemotherapy with an ABVD regimen, the condition improved during the period of review, and the left neck mass was resected in November 2018 due to the "discovery of left neck mass," and the pathology showed "consistent with the relapse of nodular sclerosing Hodgkin's lymphoma.” 2018-12-3PET-CT showed "consider lymphoma," and the pathology showed "consider lymphoma." CT showed "consider lymphoma (involving multiple cervicothoracic lymph nodes, thymic area) with FDG hypermetabolism, nodular and nodular-like foci in the upper lobes of both lungs, high metabolism, consider the possibility of involvement, recommend observation." ABVD regimen chemotherapy was given for four cycles. PET-CT efficacy evaluation at the end of treatment was CR. 2022-2-5 review PET-CT shows: 1. Combined with the history, after lymphoma treatment, mediastinum, left internal breast area, and left supraclavicular enlarged lymph nodes with hypermetabolism, PET score of 5. 2022-2-18 was admitted to our hospital and was given PD-1 (Tirilizumab) + Decitabine combined with recurrent lesion boom-boom radiotherapy (2Gy × 2 times), a total of 5 cycles of treatment, initially planned for the 1st Cycle 2 was closed due to the new crown epidemic cell. 2 cycles later 2022-4-14 review PET-CT: compared with 2022-02-05 film: 1. Combined with the history, lymphoma treatment, the original mediastinum, the left internal breast area, the left supraclavicular region of the enlarged lymph nodes with high metabolism, this image is significantly smaller than the previous, metabolism is reduced; PET score of 1–2 points. Five cycles later, 2022-6-30 review PET-CT: compared with 2022-04-14 film: 1. Combined with medical history, after lymphoma treatment, the original mediastinum, left internal breast area, left supraclavicular room enlarged lymph nodes with high metabolism, this image did not see the exact metabolism, roughly the same as the previous one; PET score of 1. Admitted to the hospital on 2022-7-14, combined with PET-CT, considering the CR status, and given autologous hematopoietic stem cell transplantation. Regular PD1 immuno-maintenance therapy was administered after that. Patient 2 was last followed up on August 8, 2023, and there were no signs of recurrence in the patient's physical condition, hematological parameters, or imaging. 4 Discussion 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 13 In 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. Declarations Acknowledgments Not applicable. Author contributions YJB、SPY、XZ、ZBK have contributed significantly to the conception or design of the work and agree to be responsible for all aspects of the work, ensuring that issues relating to the accuracy or completeness of any part of the work are properly investigated and resolved. WC draft the work and analyze and interpret the work data. Data availability The other data used and/or analyzed during the current study are available from the corresponding author on reasonable request. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding This work was supported by the following grants: National Natural Science Foundation of China (Grant No. 82272753), Shandong ProvincialNatural Science Foundation(ZR2021LZL002), Bethune Cancer Radiotherapy Translational Medicine Research Fund ( flzh202103) References Shanbhag S, Ambinder RF. Hodgkin lymphoma: A review and update on recent progress. CA Cancer J Clin. 2018;68:116–32. Kaplan HS. The Radical Radiotherapy of Regionally Localized Hodgkin’s Disease. Radiology. 1962;78:553–61. Colby TV, Hoppe RT, Warnke RA. Hodgkin’s Disease: A clinicopathologic study of 659 cases. Cancer. 1982;49:1848–58. Sher DJ, et al. Prognostic significance of mid- and post-ABVD PET imaging in Hodgkin’s lymphoma: the importance of involved-field radiotherapy. Ann Oncol. 2009;20:1848–53. Levis M, et al. Peritransplant Radiation Therapy in Patients With Refractory or Relapsed Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant: Long-Term Results of a Retrospective Study of the Fondazione Italiana Linfomi. Int J Radiat Oncol. 2023;116:1008–18. Moore C, et al. Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) in Preclinical Models Enhances Single-Agent Immune Checkpoint Blockade. Int J Radiat Oncol Biol Phys. 2021;110:1306–16. Filatenkov A, et al. Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions. Clin Cancer Res. 2015;21:3727–39. Nguyen NP, et al. Stereotactic Body Radiotherapy and Immunotherapy for Older Patients with Oligometastases: A Proposed Paradigm by the International Geriatric Radiotherapy Group. Cancers. 2022;15:244. Weber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015;33:2092–9. Timmerman R. Beyond Fractionation: PULSAR as Novel Radiotherapy Paradigm. Oncol Times. 2021;43:1. Ansell SM, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin’s Lymphoma. N Engl J Med. 2015;372:311–9. Friedman S, et al. Evolution of erythrocyte sedimentation rate as predictor of early relapse in posttherapy early-stage Hodgkin’s disease. J Clin Oncol. 1988;6:596–602. Zhu M, et al. C-reactive protein and cancer risk: a pan-cancer study of prospective cohort and Mendelian randomization analysis. BMC Med. 2022;20:301. Ahmed R, et al. The Outcome of Hodgkin Lymphoma With Reference to Prognostic Markers. Cureus. 2022. 10.7759/cureus.28421 . 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4636906","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":334833648,"identity":"f9e40f46-be22-4d5e-8842-cf5629a355d6","order_by":0,"name":"Chen Wang","email":"","orcid":"","institution":"Shandong University","correspondingAuthor":false,"prefix":"","firstName":"Chen","middleName":"","lastName":"Wang","suffix":""},{"id":334833655,"identity":"9381becb-c06c-41c4-b6c7-26ac1df1e37f","order_by":1,"name":"Zhuang Xue","email":"","orcid":"","institution":"Affiliated Cancer Hospital of Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zhuang","middleName":"","lastName":"Xue","suffix":""},{"id":334833656,"identity":"14b24f9f-5c3f-41ba-bdd8-f03165b727f6","order_by":2,"name":"Benkui Zou","email":"","orcid":"","institution":"Affiliated Cancer Hospital of Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Benkui","middleName":"","lastName":"Zou","suffix":""},{"id":334833658,"identity":"86429bd6-6a03-4c94-a5e3-8f3ca98ab5e0","order_by":3,"name":"Pengyue Shi","email":"","orcid":"","institution":"Affiliated Cancer Hospital of Shandong First Medical University","correspondingAuthor":false,"prefix":"","firstName":"Pengyue","middleName":"","lastName":"Shi","suffix":""},{"id":334833660,"identity":"1d548353-72bd-46f1-bff6-514c43b687d3","order_by":4,"name":"Jinbo Yue","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAy0lEQVRIiWNgGAWjYBACxhkgsoKBsb0BxGAjWssZBsaeA8RqYZAA6WsjRQvz7B4ziY/z6mR7xM4YMHwoO8zAP7uBgMPmnDGTnLntsHGPdI4B44xzhxkk7hwgoGVGjpk077YDifuBWph52w4zGEgkEKHl75y6RJAtzH+J1sLYwAzRwkiUljnHii17joH8klZwsOdcOo/EDQJaDGc3b7zxowYYYtLJGx/8KLOW459BSEsDhwGccwCIefCrBwJ5BvYHBBWNglEwCkbBCAcAjeJDXkmOFZUAAAAASUVORK5CYII=","orcid":"","institution":"Shandong University","correspondingAuthor":true,"prefix":"","firstName":"Jinbo","middleName":"","lastName":"Yue","suffix":""}],"badges":[],"createdAt":"2024-06-25 13:44:42","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4636906/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4636906/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":62153000,"identity":"8734a72d-8523-4aa7-948b-f3a7ccf3fcac","added_by":"auto","created_at":"2024-08-09 20:52:24","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61082,"visible":true,"origin":"","legend":"\u003cp\u003eTreatment Programs| CR, complete response\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4636906/v1/12e9476b5d97593b59a9a98a.png"},{"id":62151596,"identity":"fb29d45f-096a-447c-a964-b7952b1af8aa","added_by":"auto","created_at":"2024-08-09 20:44:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":236189,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 2.1 | Disease status timeline and scan image of abdominal lymph node lesions accompanied by treatment regimens. Point-in-time filled with red color represents the initiation of 1 cycle regimen. Patient 1 undertook a total of 6 cycles of this regimen.\u003c/p\u003e","description":"","filename":"2.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4636906/v1/ee84ab228ea39f21a17a4633.png"},{"id":62153003,"identity":"09c61991-051d-41ba-a621-c259527c13f3","added_by":"auto","created_at":"2024-08-09 20:52:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":139800,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 2.2｜(A) Hematological indexes remained stable except the number of monocytes peaked during radiotherapy; (B) MLR remained stable and then peaked during radiotherapy; (C) Serum CRP level significantly reduced after Camrelizumab and RT.(D) Serum LDH level significantly reduced after Camrelizumab and RT.｜WBC, white blood cell; N, neutrophil; L, lymphocyte; ESR Erythrocyte Sedimentation Rate; CRP, C-reactive protein; LDH Lactate dehydrogenase\u003c/p\u003e","description":"","filename":"2.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4636906/v1/b948fbc7419155e40dd4c38c.png"},{"id":62153001,"identity":"a8f2d47b-ef80-41a7-81d3-5e8d3087f0ac","added_by":"auto","created_at":"2024-08-09 20:52:24","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":263443,"visible":true,"origin":"","legend":"\u003cp\u003eFigure 3.1 | Disease status timeline and scan image of mediastinal lymph node lesions accompanied by treatment regimens. Point-in-time filled with red color represents the initiation of 1 cycle regimen. Patient 2 undertook a total of 5 cycles of this regimen.\u003c/p\u003e","description":"","filename":"3.1.png","url":"https://assets-eu.researchsquare.com/files/rs-4636906/v1/1379e14f419fe7b303760d1e.png"},{"id":64067474,"identity":"bfeca252-c2bb-4444-8735-4fcb432c5571","added_by":"auto","created_at":"2024-09-06 05:34:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":983318,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4636906/v1/6fc89500-ca0c-4480-8936-079ca2ad3b50.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Relapsed/refractory classical Hodgkin lymphoma treated with pulsed Boom-Boom radiotherapy combined with a PD-1 inhibitor and decitabine: Two case reports","fulltext":[{"header":"1 Introduction","content":"\u003cp\u003eHodgkin lymphoma (HL) is a unique hematopoietic cancer characterized by Reed-Sternberg cells. Most commonly diagnosed in the 20\u0026ndash;34 age group, it can occur across all ages. Relapse signifies the disease's return after remission, while refractory refers to treatment resistance. Secondary therapies offer remission and potential cure for relapsed or refractory cases, affecting 10\u0026ndash;30% and 5\u0026ndash;10% of patients, respectively. treatment options depend on timing, age, health, and prior therapies. Standard secondary treatment often involves combination therapy and stem cell transplantation. Despite efforts, around 50% of patients do not achieve cure with traditional salvage chemotherapy and transplantation.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Research aims to improve complete response rates pre-transplantation with novel agents.\u003c/p\u003e \u003cp\u003eInvolved site radiation therapy (ISRT) targets affected and adjacent lymph nodes. Personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) delivers radiation in pulses, offering potential benefits like tumor response to treatment changes, immune system activation, and integration with other interventions.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e Traditionally, relapsed HL is treated with salvage chemotherapy and autologous stem cell transplant (ASCT). However, some patients may not be eligible or respond poorly to this approach. This article discusses two cases of nodular sclerosing relapsed/refractory HL treated with pulsed Boom-Boom radiotherapy, a PD-1 inhibitor, and Decitabine. This combination aims to achieve complete response for ASCT, extending survival and offering an effective treatment approach for relapsed/refractory HL.\u003c/p\u003e"},{"header":"2 Method and materials","content":"\u003cp\u003eTwo patients with recurrent Hodgkin's lymphoma admitted to our department were retrospectively analyzed; both patients had advanced relapsed/refractory Hodgkin's lymphoma (nodular sclerosis type). Case 1 was found to have an abdominal mass on consultation for lower limb numbness, and case 2 was found on regular review imaging follow-up, both with a PET-CT Deauville score of 5 confirming the diagnosis of recurrent Hodgkin's lymphoma.\u003c/p\u003e \u003cp\u003ePulsed (PULSAR) Boom-Boom radiotherapy (2Gy/dose x 2f D1-2 q3w) x 6 times was administered to the recurrent lesions in combination with a DP regimen: PD-1 monoclonal antibody (200mg D0 q3w) decitabine (10mg D1-5 q3w), one cycle of treatment every 21 days, and six processes of treatment were applied(Figure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Assessed at the end of treatment, two cases were in complete remission (CR), had undergone autologous stem cell transplantation, and then entered PD-1 maintenance therapy. Now, the two patients have been treated with good results.\u003c/p\u003e"},{"header":"3 Result","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Presentation of Case #1\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePatient 1 is female and 35 years old. She was admitted to the hospital for \"Hodgkin's lymphoma diagnosed for eight years, recurrence after radiotherapy.\" On February 8, 2014, paroxysmal cough, CT showed a middle and upper mediastinal space-occupying lesion, which was consistent with the CT manifestation of the tumor and was considered to be lymphoma, with a small amount of effusion in the bilateral thoracic cavity and pericardium. Lymph node biopsy pathology: (right supraclavicular) Consider classic Hodgkin's lymphoma (nodular sclerosis type). Eight cycles of ABVD regimen, PET-CT efficacy evaluation was PR on October 18, 2014. 32.4Gy/18f of chest radiation and 40Gy of GTV were performed on October 23, 2014, and the condition improved. 2022 was admitted to the hospital on April 6, 2022, for \"numbness of the lower limbs.\" PET-CT was shown: Clinical diagnosis of Hodgkin's lymphoma after comprehensive treatment (Deauville score: 5), abdominal cavity, retroperitoneal multiple abnormal hypermetabolic occupations, considered to be lymphoma recurrence. Retroperitoneal lymph node aspiration biopsy: Consistent with classic Hodgkin's lymphoma, predisposed to nodular sclerosis type.\u003c/p\u003e \u003cp\u003eOn May 12, 2022, PD-1\u0026thinsp;+\u0026thinsp;decitabine was given with boom-boom radiotherapy to the recurrent lesion (2Gy x 2 sessions) for six treatment cycles. Two cycles later on July 7, 2022.4 Repeat PET-CT: in conjunction with the clinic, after treatment of the lymphoma recurrence, mediastinal soft tissue shadows without hypermetabolism were seen; retroperitoneal soft tissue mass and small lymph nodes with mild metabolism ( Deauville score of 3.\u003c/p\u003e \u003cp\u003eThe patient was hospitalized on August 1, 2022, due to novel coronavirus pneumonia and was discharged after four days of treatment with alleviated symptoms.4 cycles later, PET-CT on August 29, 2022: combined with clinical findings, after treatment for lymphoma relapse, mediastinal soft tissue shadow, no hypermetabolism seen; retroperitoneal soft tissue mass and small lymph nodes with mild metabolism of patchy pattern (no significant change from 2022-07-04 PET). 6 cycles later, PET-CT on October 11, 2022: In conjunction with clinical, after treatment for lymphoma relapse, mediastinal soft tissue shadow, no hypermetabolism seen; retroperitoneal soft tissue mass and small lymph nodes with patchy mild metabolism (no significant change from 2022-08-29 PET).\u003c/p\u003e \u003cp\u003eOn October 10, 2022, in conjunction with PET-CT, CR status was considered, and autologous hematopoietic stem cell transplantation was given. On 2022-10-25, autologous hematopoietic stem cell transplantation was performed. Regular PD1 immuno-maintenance therapy was performed after that. In April 2023, radiofrequency ablation of arrhythmia was performed. Patient 1 was last followed up on October 4, 2023, and there were no signs of recurrence in the patient's physical condition, hematological parameters, or imaging.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Presentation of Case #2\u003c/h2\u003e \u003cp\u003e \u003cdiv class=\"BlockQuote\"\u003e \u003cp\u003ePatient 2, female, 31 years old, presented with the following complaint: Hodgkin's lymphoma, diagnosed nine years ago, relapsed after second-line treatment. Current medical history: 2013-4-2, \"found left neck mass,\" left neck mass resection, pathology: (left supraclavicular) classic Hodgkin's lymphoma, nodular sclerosis type. 2013-4-5, admitted to our hospital, PET-CT: lymphoma bilateral lower neck, double clavicular region, mediastinum, internal breast area multiple lymph node involvement, proper femoral neck involvement with FDG hypermetabolism. Femoral neck involvement with FDG hypermetabolism. After eight cycles of chemotherapy with an ABVD regimen, the condition improved during the period of review, and the left neck mass was resected in November 2018 due to the \"discovery of left neck mass,\" and the pathology showed \"consistent with the relapse of nodular sclerosing Hodgkin's lymphoma.\u0026rdquo; 2018-12-3PET-CT showed \"consider lymphoma,\" and the pathology showed \"consider lymphoma.\" CT showed \"consider lymphoma (involving multiple cervicothoracic lymph nodes, thymic area) with FDG hypermetabolism, nodular and nodular-like foci in the upper lobes of both lungs, high metabolism, consider the possibility of involvement, recommend observation.\" ABVD regimen chemotherapy was given for four cycles. PET-CT efficacy evaluation at the end of treatment was CR.\u003c/p\u003e \u003cp\u003e2022-2-5 review PET-CT shows: 1. Combined with the history, after lymphoma treatment, mediastinum, left internal breast area, and left supraclavicular enlarged lymph nodes with hypermetabolism, PET score of 5. 2022-2-18 was admitted to our hospital and was given PD-1 (Tirilizumab)\u0026thinsp;+\u0026thinsp;Decitabine combined with recurrent lesion boom-boom radiotherapy (2Gy \u0026times; 2 times), a total of 5 cycles of treatment, initially planned for the 1st Cycle 2 was closed due to the new crown epidemic cell. 2 cycles later 2022-4-14 review PET-CT: compared with 2022-02-05 film: 1. Combined with the history, lymphoma treatment, the original mediastinum, the left internal breast area, the left supraclavicular region of the enlarged lymph nodes with high metabolism, this image is significantly smaller than the previous, metabolism is reduced; PET score of 1\u0026ndash;2 points. Five cycles later, 2022-6-30 review PET-CT: compared with 2022-04-14 film: 1. Combined with medical history, after lymphoma treatment, the original mediastinum, left internal breast area, left supraclavicular room enlarged lymph nodes with high metabolism, this image did not see the exact metabolism, roughly the same as the previous one; PET score of 1. Admitted to the hospital on 2022-7-14, combined with PET-CT, considering the CR status, and given autologous hematopoietic stem cell transplantation. Regular PD1 immuno-maintenance therapy was administered after that. Patient 2 was last followed up on August 8, 2023, and there were no signs of recurrence in the patient's physical condition, hematological parameters, or imaging.\u003c/p\u003e \u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4 Discussion","content":"\u003cp\u003eHodgkin 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.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCombined 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.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003ePULSAR (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\u0026thinsp;+\u0026thinsp;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.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e 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. \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e They used similar pre-clinical models and further demonstrated mechanistically that CD8\u0026thinsp;+\u0026thinsp;T cell infiltration into tumors is hindered after repeated 3Gy daily doses, an essential predictor of immunotherapy response in humans.\u003c/p\u003e \u003cp\u003eIn 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.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e 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.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e 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.\u003c/p\u003e \u003cp\u003eDecitabine, 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).\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eInflammatory 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.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e CRP is recognized as a potential biomarker for assessing cancer risk and has been validated in 12 site-specific cancers \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003eIn 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.\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e2.2\u003c/span\u003e)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.\u003c/p\u003e \u003cp\u003eThis 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.\u003c/p\u003e \u003cp\u003eClinical trials evaluating this treatment regimen are undergoing ethical review.\u003c/p\u003e \u003cp\u003e 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.\u003c/p\u003e \u003cp\u003eAll 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.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYJB、SPY、XZ、ZBK have contributed significantly to the conception or design of the work and agree to be responsible for all aspects of the work, ensuring that issues relating to the accuracy or completeness of any part of the work are properly investigated and resolved. WC draft the work and analyze and interpret the work data.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe other data used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the following grants: National Natural Science Foundation of China (Grant No. 82272753), Shandong ProvincialNatural Science Foundation(ZR2021LZL002), Bethune Cancer Radiotherapy Translational Medicine Research Fund ( \u0026nbsp;flzh202103)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShanbhag S, Ambinder RF. Hodgkin lymphoma: A review and update on recent progress. CA Cancer J Clin. 2018;68:116\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaplan HS. The Radical Radiotherapy of Regionally Localized Hodgkin\u0026rsquo;s Disease. Radiology. 1962;78:553\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eColby TV, Hoppe RT, Warnke RA. Hodgkin\u0026rsquo;s Disease: A clinicopathologic study of 659 cases. Cancer. 1982;49:1848\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSher DJ, et al. Prognostic significance of mid- and post-ABVD PET imaging in Hodgkin\u0026rsquo;s lymphoma: the importance of involved-field radiotherapy. Ann Oncol. 2009;20:1848\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLevis M, et al. Peritransplant Radiation Therapy in Patients With Refractory or Relapsed Hodgkin Lymphoma Undergoing Autologous Stem Cell Transplant: Long-Term Results of a Retrospective Study of the Fondazione Italiana Linfomi. Int J Radiat Oncol. 2023;116:1008\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoore C, et al. Personalized Ultrafractionated Stereotactic Adaptive Radiotherapy (PULSAR) in Preclinical Models Enhances Single-Agent Immune Checkpoint Blockade. Int J Radiat Oncol Biol Phys. 2021;110:1306\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFilatenkov A, et al. Ablative Tumor Radiation Can Change the Tumor Immune Cell Microenvironment to Induce Durable Complete Remissions. Clin Cancer Res. 2015;21:3727\u0026ndash;39.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNguyen NP, et al. Stereotactic Body Radiotherapy and Immunotherapy for Older Patients with Oligometastases: A Proposed Paradigm by the International Geriatric Radiotherapy Group. Cancers. 2022;15:244.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWeber JS, Yang JC, Atkins MB, Disis ML. Toxicities of Immunotherapy for the Practitioner. J Clin Oncol. 2015;33:2092\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTimmerman R. Beyond Fractionation: PULSAR as Novel Radiotherapy Paradigm. Oncol Times. 2021;43:1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAnsell SM, et al. PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin\u0026rsquo;s Lymphoma. N Engl J Med. 2015;372:311\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFriedman S, et al. Evolution of erythrocyte sedimentation rate as predictor of early relapse in posttherapy early-stage Hodgkin\u0026rsquo;s disease. J Clin Oncol. 1988;6:596\u0026ndash;602.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhu M, et al. C-reactive protein and cancer risk: a pan-cancer study of prospective cohort and Mendelian randomization analysis. BMC Med. 2022;20:301.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAhmed R, et al. The Outcome of Hodgkin Lymphoma With Reference to Prognostic Markers. Cureus. 2022. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7759/cureus.28421\u003c/span\u003e\u003cspan address=\"10.7759/cureus.28421\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4636906/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4636906/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eHodgkin lymphoma (HL), characterized by cancerous Reed-Sternberg cells within an inflammatory milieu, poses challenges in relapsed or refractory cases. Current standard treatments, including salvage chemotherapy and autologous stem cell transplantation (ASCT), have limitations in achieving long-term remission. Herein, we present two cases of nodular sclerosing relapsed/refractory Hodgkin's lymphoma treated with personalized ultrafractionated stereotactic adaptive radiotherapy (PULSAR) in combination with a PD-1 inhibitor and Decitabine. Patients underwent PULSAR (2Gy/dose x 2f D1-2 q3w) for recurrent lesions along with PD-1 monoclonal antibody (200mg D0 q3w) and Decitabine (10mg D1-5 q3w) for six cycles. Both patients achieved complete remission (CR) post-treatment, enabling subsequent ASCT and PD-1 maintenance therapy. Follow-up revealed prolonged survival without recurrence. PULSAR, by delivering radiation pulses at longer intervals, allows for tumor adaptation and immune response, potentially enhancing treatment efficacy and minimizing toxicity. Combined with immunotherapy and Decitabine, PULSAR shows promise in managing relapsed/refractory HL, warranting further investigation through clinical trials. This approach signifies a paradigm shift towards precision tumor therapy and immunomodulation in HL management.\u003c/p\u003e","manuscriptTitle":"Relapsed/refractory classical Hodgkin lymphoma treated with pulsed Boom-Boom radiotherapy combined with a PD-1 inhibitor and decitabine: Two case reports","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-09 20:44:19","doi":"10.21203/rs.3.rs-4636906/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"85bdc0d8-71a2-404c-b6d5-d786614396f7","owner":[],"postedDate":"August 9th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-09-06T05:26:52+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-09 20:44:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4636906","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4636906","identity":"rs-4636906","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}