Treatment Of Hodgkin Lymphoma Research Articles

Tolerability and efficacy of BrECADD versus BEACOPP in advanced stage classical Hodgkin lymphoma: GHSG HD21, a randomized study.

LBA7000 Background: We hypothesized that therapy with the novel BrECADD regimen (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, dexamethasone) guided by positron emission tomography after two cycles (PET2) could improve the treatment of advanced-stage classical Hodgkin lymphoma (AS-cHL). The HD21 trial aimed at demonstrating superiority over the intensified BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in terms of treatment-related morbidity (TRMB) and non-inferiority (NI) in terms of progression-free survival (PFS). This is the first report of the final confirmative analysis of the HD21 trial. Methods: HD21 is an international, open-label, randomized phase III trial including AS-cHL patients 18-60 years at diagnosis. Patients were randomized to receive individualized 4 or 6 cycles of either BEACOPP or BrECADD guided by PET2 results. The co-primary endpoints included TRMB and PFS, which had been successfully established recently. Testing for superiority was planned with mature follow-up of four years. An adjusted alpha level of 0.047 was required to cross the efficacy boundary for superiority. The trial was conducted in accordance with ICH-GCP (NCT02661503) and supported by a research grant from Takeda Oncology. Results: The ITT (intention-to-treat) cohort for the efficacy analysis consisted of 1482 patients, of which 742 were randomized to receive BrECADD and 740 to BEACOPP. Median age was 31.1 years (range 18 to 60), 44% were female. PET2 was negative in 424 (57.5%) and 426 (58.2%) patients for BrECADD or eBEACOPP, respectively, and these were scheduled for 4 treatment cycles. With median follow-up of 48 months, 4y-PFS was 94.3% for BrECADD (95%-CI 92.6-96.1), and 90.9% for BEACOPP (95%-CI 88.7-93.1). The hazard ratio was 0.66 [95% CI 0.45-0.97], p=0.035). PFS benefit of BrECADD was driven by a reduction in early treatment failures, i.e., primary progression within 3 months (5 vs. 15) or early relapse between months 3 and 12 (11 vs. 23) and observed across all investigated subgroups. PET2-negative patients in the BrECADD group showed a 4-year PFS of 96.5%. 4-year OS was 98.5% for BrECADD and 98.2% for BEACOPP. Analyses of gonadal function demonstrated significantly higher follicle stimulating hormone recovery rates after one year in both men (67% vs. 24%) and women (89% vs. 68%) with higher birth-rates in the BrECADD group (n=60 vs. n=43). Conclusions: BrECADD is significantly more effective than BEACOPP and is associated with an unprecedentedly high 4-year PFS, reducing the risk of progression, relapse or death by a third. Together with an abbreviated treatment duration of only 3 months for the majority of patients and a favorable tolerability, treatment with PET2-individualized BrECADD sets a new benchmark for the treatment of adult patients with AS-cHL. Clinical trial information: NCT02661503 .

Correction: Current Standards in the Treatment of Hodgkin Lymphoma

Correction: Current Standards in the Treatment of Hodgkin Lymphoma

Paradigm Shifts in Hodgkin Lymphoma Treatment: From Frontline Therapies to Relapsed Disease.

Combination chemotherapy with or without radiation has served as the primary therapeutic option for classic Hodgkin lymphoma (cHL), leading to durable remission in a majority of patients with early- and advanced-stage cHL. Patients with relapsed/refractory (RR) cHL could still be cured with salvage chemotherapy and autologous stem-cell transplantation. Brentuximab vedotin (BV) and the anti-PD-1-blocking antibodies, nivolumab and pembrolizumab, are highly effective treatments for cHL and have revolutionized the management of the disease. Recent studies incorporating BV and PD-1 blockade into salvage therapy for RR cHL and into frontline treatment regimens have changed the cHL treatment paradigm. The novel agents are also useful in the treatment of older patients who have poor outcomes with traditional therapy. This manuscript will review current strategies for approaching the management of previously untreated, RR, and challenging populations with cHL, including how to incorporate the novel agents.

Pediatric and Adolescent Hodgkin Lymphoma: Paving the Way for Standards of Care and Shared Decision Making.

Hodgkin lymphoma (HL) is a treatable cancer with an incidence peak in adolescent and young adult years. Treatment strategies have been developed to balance the intensity of therapy needed to maintain disease-free survival while simultaneously preserving overall survival. Risk-based, response-adapted frontline therapy has long used a combination of chemotherapy and radiotherapy (RT). Successive clinical trials over the past three decades have safely reduced cumulative alkylator, anthracycline, and RT exposures for many patients. The advent of checkpoint inhibitors and the CD30-targeted antibody drug conjugate, brentuximab vedotin, has provided new options for de-escalation of conventional therapies associated with late effects in survivors treated at a young age. The ability to evaluate novel agents has been accelerated in collaborative trials inclusive of children and adolescents within the US National Clinical Trials Network and between the Children's Oncology Group and the EuroNet Pediatric Hodgkin Lymphoma Consortium. With numerous treatment options, patients with HL and their clinicians have an opportunity for shared decision making from diagnosis, through cancer treatment, and into survivorship. Given excellent survival outcomes, decisions about treatment in classic HL should be collaborative and attention to long-term survivorship needs should remain a high priority. Patient-reported outcomes remain an important tool to aid clinicians working with survivors to optimize health status and related quality of life for decades after HL therapy.

Contemporary radiation therapy use in Hodgkin lymphoma

Radiation therapy assumes a pivotal role in Hodgkin lymphoma management, especially within combined modality therapy. It serves as a cornerstone in early-stage disease and in mitigating high-risk instances of local relapse in advanced stages. Over recent decades, radiation therapy has undergone significant advancements, notably alongside diagnostic imaging improvements, facilitating the reduction of radiation field size and dosage. This progress has notably led to minimized toxicity while upholding treatment efficacy.This comprehensive review extensively evaluates the indications and advancements in radiation therapy for Hodgkin lymphoma, with a primary focus on enhancing treatment efficacy while minimizing radiation-related toxicities. The exploration encompasses a detailed examination of various radiation fields, techniques and delivery modalities employed in Hodgkin lymphoma treatment, including intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and proton therapy. It delves into the intricacies of optimal dose selection and treatment planning strategies aimed at achieving maximal disease control while concurrently minimizing the risk of long-term side effects.

Treatment Strategies in Advanced-Stage Hodgkin Lymphoma.

The last 3 decades have witnessed a major evolution in the treatment of advanced-stage Hodgkin lymphoma (HL). The most prominent of these developments include the introduction of the international prognostic scoring (IPS) system; therapeutic decision-making based on both IPS and interim PET/CT data; the finding that a negative interim PET/CT result could be safely used for treatment de-escalation; the introduction of intensive combination chemotherapy like escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, oncovin (vincristine), procarbazine, and prednisone); and further modification of this protocol with the incorporation of a conjugated anti-CD30 antibody brentuximab vedotin (BV) into first-line regimens, like BV-AVD (BV+ adriamycin, vinblastine and dacarbazine) and BrECADD (brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone). The accruing data about the toxicity of the escalated BEACOPP protocol have led to decreasing the number of therapeutic cycles, substitution of toxic agents like procarbazine with dacarbazine (e.g., BEACOPDac), and reduction/omission of radiation therapy. Lately, a significant advancement has been made by the integration of checkpoint inhibitors in the first-line treatment, with preliminary results demonstrating the superiority of anti-PD1 combined with chemotherapy (nivolumab-AVD) compared to the BV-AVD regimen. This review aims to analyze recently published studies whose findings could change the treatment practice in advanced-stage HL.

The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. N/A.

Current Standards in the Treatment of Hodgkin Lymphoma

This review discusses current trends in the treatment of Hodgkin lymphoma, focusing on optimizing therapy outcomes while minimizing toxicity. We summarize advances made by the incorporation of Brentuximab Vedotin into first line therapy for advanced stage Hodgkin lymphoma. Similarly, the incorporation of checkpoint-inhibition into first-line therapy holds great promise and early results suggest superior efficacy with reduced toxicity. In relapsed or refractory Hodgkin lymphoma, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation remains the standard approach. However, the remarkable efficacy of checkpoint inhibition in this setting has the potential to redefine treatment paradigms and obviate the need for HD-ASCT in select patients. Finally, we discuss the evolving landscape of nodular lymphocyte predominant Hodgkin lymphoma and reclassification to nodular lymphocyte predominant B-cell lymphoma, with increasing recognition of its distinct characteristics and treatment strategies.

Advances in Hodgkin Lymphoma Treatment: From Molecular Biology to Clinical Practice.

Classical Hodgkin Lymphoma (cHL) is a highly curable disease, but around 20% of patients experience progression or relapse after standard frontline chemotherapy regimens. Salvage regimens followed by autologous stem cell transplants represent the historical treatment approach for these cases. In the last decade, with the increasing understanding of cHL biology and tumor microenvironment role in disease course, novel molecules have been introduced in clinical practice, improving outcomes in the relapsed/refractory setting. The anti-CD30 antibody-drug conjugated brentuximab vedotin and PD-1/PD-L1 checkpoint inhibitors represent nowadays curative options for chemorefractory patients, and randomized trials recently demonstrated their efficacy in frontline immune-chemo-combined modalities. Several drugs able to modulate the patients' T-lymphocytes and NK cell activity are under development, as well as many anti-CD30 chimeric antigen receptor T-cell products. Multiple tumor aberrant epigenetic mechanisms are being investigated as targets for antineoplastic compounds such as histone deacetylase inhibitors and hypomethylating agents. Moreover, JAK2 inhibition combined with anti-PD1 blockade revealed a potential complementary therapeutic pathway in cHL. In this review, we will summarize recent findings on cHL biology and novel treatment options clinically available, as well as promising future perspectives in the field.

Abstract PO4-27-11: Fat grafting is oncologically safe during implant-based breast reconstruction and mastectomy after radiotherapy for breast cancer or Hodgkin Lymphoma: results of a multicentric study

Abstract Background. Fat grafting during or after mastectomy could promote the regeneration of irradiated tissues, thus improving tissue softness, increasing patient comfort and ameliorating quality of life. However, there are no conclusive data about the oncological safety of fat grafting, especially in terms of risk of tumor recurrences. The most appropriate timing of adipose tissue transplant is also debated, especially in patients with locoregional breast cancer (BC) recurrence undergoing salvage mastectomy and implant-based breast reconstruction after breast conserving surgery and radiotherapy. Methods. We conducted a prospective, multicentric Italian study to investigate the oncological safety of fat grafting between June 2007 and March 2022. One hundred sixty-three patients who had previously received radiotherapy, either as adjuvant treatment after breast conservative surgery (N=154), or as a treatment of Hodgkin Lymphoma (N=9), underwent mastectomy (simple mastectomy, NAC-sparing and skin-sparing mastectomy) and implant-based, two-stage breast reconstruction. Inclusion criteria were: age between 25 and 75 years, absence of concomitant malignancies, grade 2 or 3 of Breast post Radiotherapy Reconstruction with ExpAnder Score Test (B.R.R.E.A.S.T. score) (Tab 1). Patient BMI, hypertension, smoking history, diabetes and having received neoadjuvant chemotherapy were not considered as exclusion criteria. Contextual mastectomy and expander positioning were performed during first stage (stage I), while substitution of the expander with definitive implant occurred during second stage (stage II). Fat grafting could be performed during stage I, between stage I and II surgery, or during stage II. Results. One hundred sixty-nine mastectomy procedures (six bilateral) and first-stage implant-based reconstructions with expander were performed either as prophylactic surgery (N=23) or for the treatment of primary or recurrent BC (N=146). Thirty-four patients had ductal carcinoma in situ, whereas 112 patients had invasive disease, including: 17 patients with Luminal A BC, 67 patients with Luminal B HER2-negative BC, 3 patients with Luminal B HER-2 positive BC, 7 patients with HER-2 positive BC and 18 patients had triple-negative BC. One hundred thirty-six (80.5%) patients received at least one fat grafting. Eighty-six patients (52.8%) have received second-stage definitive implant. With a median time of observation of 25.1 months, we observed four locoregional cancer recurrences (2.4%), one of which in axillary lymph nodes. All tumor recurrences occurred in patients who had received fat grafting. Eight patients (4.9%) developed distant metastases (liver, lung, lymph nodes, and bone metastases); of these, four patients (50%) had received fat grafting. No death events occurred. Conclusion. Fat grafting after radiotherapy of the breast is associated with a low incidence of locoregional tumor recurrences and distant metastases. Although our findings need to be confirmed in larger, multicentric clinical studies, fat grafting is a safe and useful technique that can be proposed for breast reconstruction after irradiation. Table. Breast post Radiotherapy Reconstruction with ExpAnder Score Test, B.R.R.E.A.S.T score. Based on our experience, we thought to include two tissue characteristics (Pinch test ≥ 0.5 cm and presence/absence of skin teleangectasia or severe dyscromia) in a pre-operative, clinically useful, and ready-to-use score to assess soft tissue adequacy as recommended by NCCN guidelines, that we called Breast post Radiotherapy Reconstruction with ExpAnder Score Test (B.R.R.E.A.S.T. score). In our study, two-stage implant-based breast reconstruction and adipose tissue transplant with regenerative intent were performed in patients with Pinch test ≥ 0.5 cm but moderate skin teleangectasia or dyscromia (B.R.R.E.A.S.T. score 2) and in patients with Pinch test ≥ 0.5 cm and absence of skin teleangectasia or severe dyscromia (B.R.R.E.A.S.T. score 3). Patients with skin teleangectasia or dyscromia and Pinch test &amp;lt; 0.5 cm (B.R.R.E.A.S.T. score 1) were not enrolled in our study as they did not undergo alloplastic breast reconstruction but they underwent autologous reconstruction (data not shown). Citation Format: Chiara Listorti, Claudio Vernieri, Francesco Barretta, Chiara Osio, Ilaria Maugeri, Federica Pilotta, Cristina Ferraris, Massimiliano Gennaro, Gabriele Martelli, Marco Visaggio, Giulia Valeria Bianchi, Serena Di Cosimo, Gianfranco Scaperrotta, Maria Carmen De Santis, Daniela Tognali, Antonino Romeo, Matteo Mingozzi, Francesco Marongiu, Annalisa Curcio, Secondo Folli. Fat grafting is oncologically safe during implant-based breast reconstruction and mastectomy after radiotherapy for breast cancer or Hodgkin Lymphoma: results of a multicentric study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-27-11.

Recent updates in the therapeutic uses of Pembrolizumab: a brief narrative review.

Treatment of cancer has been improved with the discovery of biological drugs that act as immune checkpoint inhibitors. In 2017, FDA designated pembrolizumab, an immune checkpoint inhibitor employed in immunotherapy, as the first tissue-agnostic cancer treatment. To review pembrolizumab's use in oncology, gather and examine the latest discoveries regarding the effectiveness of pembrolizumab in cancer treatment. A literature review was conducted through PubMed(Medline) from January 2015 to December 2023 using "pembrolizumab", "cancer" and "treatment" as search terms. Pembrolizumab demonstrated effectiveness as primary treatment for metastatic nonsmall cell lung cancer, unresectable esophageal cancer, head and neck squamous cell carcinoma and alternative treatment for notable triple-negative breast cancer, biliary, colorectal, endometrial, renal cell, cervical carcinoma, and high microsatellite instability or mismatch repair deficiencies tumors. Pediatric applications include treatment for refractory Hodgkin lymphoma. Evolving research on pembrolizumab allows a deeper clinical understanding, despite challenges as variable patient responses. Pembrolizumab has emerged as a pivotal breakthrough in cancer treatment, improving patient outcomes and safety.

The Class I Histone Deacetylase Inhibitor as a Potent Therapeutic Target for Treating Glioblastoma and Mocetinostat as a Novel Inhibitor in the Induction Death of Cancer Cells

Epigenetic abnormality is one of the hallmarks of glioblastoma cancer cells. Histone deacetylase (HDAC) modification has a crucial role in epigenetic abnormality, which results in the initiation and progression of glioblastoma cancer cells. The selective HDAC inhibitors are well-known epigenetic regulators and promising anti-cancer agents that target specific HDAC enzymes and inhibit the proliferation of many cancer cells. Selective HDAC inhibitors isoform provides a high efficacy as chemotherapy in inhibiting cancer confirmation compared to non-selective HDAC inhibitors. Additionally, selective HDAC inhibitors suppress Class -I HDAC1, HDAC2, HDAC3, and HDAC11. HDAC class I inhibitors induce apoptosis, differentiation, autophagic death cells, and reactive oxygen species (ROS)- induced cell death, inhibit cell migration, invasion, and angiogenesis in cancer cells, while the normal cells showed more resistance to HDAC class I inhibitors. Mocetinostat (MGCD0103), a benzamide histone deacetylase, is a potent anti-cancer therapy for the treatment of several cancer cell lines and induction of autophagy. It has been approved by The Food and Drug Administration (FDA) for the treatment of Hodgkin lymphoma (HL) cell lines. MGCD0103 is a synthesized and selective HDAC inhibitor that has vigorous inhibitory activity against Class-I and IV HDAC. MGCD0103 is well tolerated and has favorable pharmacokinetic properties, pharmacodynamic profile, and fast absorption within 1 hour after oral administration, long elimination half-life, and sustained HDAC inhibition. Therefore, MGCD0103 is expected to be a promising anti-cancer drug for treating several types of human cancer cells. Keywords: MGCD0103; Apoptosis; Differentiation; Gliblastoma; HDAC; inhibitors.

Effectiveness and Cost-Effectiveness of Survivorship Care for Survivors of Hodgkin Lymphoma (INSIGHT Study): Protocol for a Multicenter Retrospective Cohort Study With a Quasi-Experimental Design.

Hodgkin lymphoma (HL) occurs at young ages, with the highest incidence between 20 and 40 years. While cure rates have improved to 80%-90% over the past decades, survivors of HL are at substantial risk of late treatment-related complications, such as cardiovascular diseases, breast cancer, severe infections, and hypothyroidism. To reduce morbidity and mortality from late treatment effects, the Dutch Better care after lymphoma, Evaluation of long-term Treatment Effects and screening Recommendations (BETER) consortium developed a survivorship care program for 5-year survivors of HL that includes risk-based screening for and treatment of (risk factors for) late adverse events. Even though several cancer survivorship care programs have been established worldwide, there is a lack of knowledge about their effectiveness in clinical practice. The Improving Nationwide Survivorship care Infrastructure and Guidelines after Hodgkin lymphoma Treatment (INSIGHT) study evaluates whether Dutch BETER survivorship care for survivors of HL decreases survivors' burden of disease from late adverse events after HL treatment and associated health care costs and improves their quality of life. The INSIGHT study is a multicenter retrospective cohort study with a quasi-experimental design and prospective follow-up, embedded in the national BETER survivorship care infrastructure. The first BETER clinics started in 2013-2016 and several other centers started or will start BETER clinics in 2019-2024. This allows us to compare survivors who did and those who did not receive BETER survivorship care in the last decade. Survivors in the intervention group are matched to controls (n=450 per group) based on sex, age at diagnosis (±5 years), age in 2013 (±5 years), and treatment characteristics. The primary outcome is the burden of disease in disability-adjusted life years from cardiovascular disease, breast cancer, severe infections, and hypothyroidism. In a cost-effectiveness analysis, we will assess the cost of BETER survivorship care per averted or gained disability-adjusted life year and quality-adjusted life year. Secondary outcomes are BETER clinic attendance, adherence to screening guidelines, and knowledge and distress about late effects among survivors of HL. Study data are collected from a survivor survey, a general practitioner survey, medical records, and through linkages with national disease registries. The study was funded in November 2020 and approved by the institutional review board of the Netherlands Cancer Institute in July 2021. We expect to finalize recruitment by October 2024, data collection by early 2025, and data analysis by May 2025. INSIGHT is the first evaluation of a comprehensive survivorship program using real-world data; it will result in new information on the (cost-)effectiveness of survivorship care in survivors of HL in clinical practice. The results of this study will be used to improve the BETER program where necessary and contribute to more effective evidence-based long-term survivorship care for lymphoma survivors. PRR1-10.2196/55601.

Immune checkpoint inhibitors in advanced and relapsed/refractory Hodgkin lymphoma: current applications and future prospects.

Classic Hodgkin lymphoma (cHL) treatment paradigms are undergoing a shift with the integration of immune checkpoint inhibitors (ICIs) into both first-line and relapsed/refractory (R/R) regimens. In first-line therapy, the synergy between ICIs and chemotherapy may surpass the previous standards of ABVD and BV-AVD established by landmark trials including RATHL and ECHELON-1. In R/R disease, the combination of ICIs with chemotherapy has begun to challenge the paradigm of chemotherapy as a bridge to consolidative autologous stem cell transplantation. The clinical advances heralded by ICI offer unique challenges to management. ICI treatment and the associated inflammatory response can make the traditional timing and modalities of treatment response assessment difficult to interpret. In contrast to ABVD and BV-AVD, pembrolizumab-AVD results in PET2 positivity rates that are higher and less predictive of treatment response even when ultimate outcomes may be superior. This suggests that the predictive value of PET2 may be less reliable in the ICI era, prompting a reevaluation of response assessment strategies. Looking forward, circulating tumor DNA (ctDNA) may be a promising tool in response-adapted therapy. Its potential to complement or even supersede PET scans in predicting response to ICIs represents a critical advancement. The integration of ctDNA analysis holds the promise of refining response-adapted approaches and enhancing precision in therapeutic decision-making for patients with cHL. This review navigates the evolving landscape of cHL therapy, emphasizing the paradigmatic shift brought about by ICIs. This article explores the impact of combining ICIs with chemotherapy in both relapsed/refractory and first-line settings, scrutinizes the challenges posed to response-adapted therapy by ICIs, and highlights the potential role of ctDNA as an adjunct in refining response-adapted strategies for cHL.

Current Immunotherapy Progress in the Hodgkin Lymphoma

Hodgkin lymphoma, a distinctive cancer affecting the lymphatic system, poses challenges in treatment due to its unique characteristics and the limitations of traditional therapies. This essay delves into the potential of immunotherapy to transform the landscape of treatment for Hodgkin lymphoma. Furthermore, the essay analyses case studies to illustrate the efficacy of these approaches. It presents an overview of the underlying principles, as well as specific immunotherapeutic approaches, such as checkpoint inhibitors, monoclonal antibodies, and CAR-T cell therapy, and their mechanisms. Immunotherapy offers a targeted and personalized alternative to conventional chemotherapy and radiation, presenting promising results in clinical trials. Clinicians manage subtleties in immune-related toxicity and response assessment as the field develops. The goal of immunotherapy research in the initial phases of treatment is to increase cure rates while lowering long-term dangers. Ongoing research and advancements, including checkpoint blockade studies, offer hope for refining treatment approaches and optimizing outcomes in Hodgkin lymphoma. This essay emphasizes the significance of immunotherapy in providing effective and less toxic alternatives, heralding a new era in Hodgkin lymphoma treatment.

Successful treatment of paediatric refractory Hodgkin lymphoma with immunotherapy - A case report and literature review.

To describe a rare case of primary refractory Hodgkin lymphoma nodular sclerosis syncytial variant in a child and review immunotherapy in relapsed/refractory Hodgkin lymphoma. We described the treatment course of a child with primary refractory classic Hodgkin lymphoma and discussed different options for salvage therapy, with an emphasis on immunotherapy. We searched PubMed for all published clinical trials investigating immunotherapy in classic Hodgkin lymphoma written in English until 31 June, 2023. The reference list of each identified paper was searched for additional publications. Our patient was salvaged with anti-programmed cell death 1 (PD-1) antibody therapy followed by high-dose chemotherapy with autologous stem cell rescue. Radiotherapy was avoided. We identified five one-armed phase II trials investigating anti-PD-1 therapy in first relapse/refractory disease in a total of 254 patients aged 9-71 years, of which one included 31 children. The complete remission rate before high-dose chemotherapy was 59%-95% overall and 67%-89% among those with refractory disease. Although it remains to be proven in randomised trials, anti-PD-1 therapy may provide higher complete response rates than traditional chemotherapy. Anti-PD-1 therapy has the potential to increase the chance of cure while decreasing the risk of late effects from chemotherapy and radiotherapy.

Involved-site Radiation Therapy is Equally Effective and Less Toxic Than Involved-field Radiation Therapy in Patients Receiving Combined Modality Treatment for Early-stage Unfavorable Hodgkin Lymphoma—An Analysis of the Randomized Phase 3 HD17 Trial of the German Hodgkin Study Group

PurposeCombined modality treatment (CMT) with chemotherapy followed by consolidation radiotherapy (RT), provides excellent outcomes for patients with early-stage Hodgkin lymphoma (HL). The international standard of care for consolidation RT, involved-site/involved-node radiotherapy (ISRT/INRT), has never been evaluated in a randomized phase III trial against the former standard involved-field radiotherapy (IFRT). Methods and materialsIn the multicenter phase III AnonymizedStudyGroupXXX AnonymizedStudyYYY trial, patients with early stage unfavorable HL were randomized between the standard CMT group and a positron-emission tomography (PET) -guided group. In the standard group, patients received two cycles of escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) and two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) followed by 30 Gray (Gy) IFRT. In the experimental group patients received no further therapy if post-chemotherapy PET was negative, and 30 Gy AnonymizedStudyGroupXXX -INRT, comparable and therefore termed here ISRT, if PET was positive. Here, we analyze the interim PET positive patients in a post hoc analysis, and therefore the randomized comparison of IFRT versus INRT/ISRT. Results1,100 patients were randomized, of which 311 had a positive PET after chemotherapy. Kaplan-Meier estimates of 4-year progression-free survival (PFS) were 96.8 % (95% CI: 91.6% – 98.8%) in the IFRT group and 95.4% (95% CI: 89.9% – 97.9%; HR: 1.40, 95% CI: 0.44 – 4.42) in the ISRT group. Pattern of recurrence analyses indicated that none of the cases of disease progression or recurrence in the ISRT group would have been prevented by the use of IFRT. Acute grade III/IV toxicities occurred in 8.5% of IFRT patients and 2.6% of ISRT patients (p=0.03). ConclusionsFor the first time, consolidation INRT/ISRT was randomly compared to IFRT in a phase III trial. Regarding PFS, no advantage for IFRT could be demonstrated. In summary, our data confirm the place of INRT/ISRT as the current standard of care.

Роль полиморфных вариантов генов цитохромов Р450, а также генов GSTP1 и MDR1 в развитии токсических осложнений при проведении программной противоопухолевой лекарственной терапии у пациентов с классической лимфомой Ходжкина

Background. Although considerable progress has been achieved in the treatment of classical Hodgkin lymphoma (cHL), toxic complications of program drug chemotherapy remain an issue. Standard cytostatic agents used in cHL therapy are metabolized in liver by the enzymes with Р450 cytochrome and GSTP1 gene-controlled synthesis. At the same time, the excretion of active metabolites of antitumor drugs is mediated by MDR1 coded P-glycoprotein. Polymorphisms[1] of these genes may change the processes of antitumor drug biotransformation and their metabolite excretion. Additionally, they may result in organo-toxic complications, disablement of patients, and even death.&#x0D; Aim. To assess the role of polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1 in organ toxicity dynamics during program chemotherapy (CT) in cHL patients.&#x0D; Materials &amp; Methods. The study enrolled 122 cHL patients treated with first-line regimens (ABVD, BEACOPP) of program drug chemotherapy. The patients were aged 18–78 years (median 35 years); there were 67 (54.9 %) women and 55 (45.1 %) men. In compliance with the NCCN CTC (2003) criteria of hepatotoxicity and practical recommendations for correcting cardiovascular toxicity of chemotherapy (2021), the signs of toxic liver and heart damage were assessed in all patients. PCR was used to analyze polymorphisms in cytochrome genes Р450 as well as genes GSTP1 and MDR1, their association with toxic complications of CT was analyzed.&#x0D; Results. Drug-induced liver damage on program CT was identified in 80 % of cHL patients. The toxicity was increasing from CT cycle 1 to cycle 6 both on ABVD and BEACOPP. Complications grade 3/4 were observed only in BEACOPP recipients. Significant (p &lt; 0.05) associations were found between hepatotoxic complications with increased cytolytic (AST, ALT) and cholestatic (ALP) values and polymorphic variants of MDR1. Significant (p &lt; 0.05) reduction of left ventricle myocardium contractility in cHL patients was associated with Т-allele presence in genotypes CYP2D6*10 (rs1065852), CYP2C9*2 (rs1799853) and A-allele deletion in genotype CYP2D6_3 (rs4986774).&#x0D; Conclusion. The identification of genetic predictors for toxic effects of program CT in cHL patients at the baseline examination can minimize the risks of drug chemotherapy-related adverse events and allow these patients to maintain a satisfactory quality of life.&#x0D; &#x0D; [1] Gene polymorphism is a structural difference between alternative variants of a gene. Alternative variants of genes result from mutations.

The Opposite Functions of CD30 Ligand Isoforms.

TNFSF8/CD30 ligand is a TNF superfamily member expressed on several major immune cell types, including activated monocytes, B, and T cells. The signaling of CD30 ligand through its cognate CD30 receptor has been shown to have effects on cell differentiation, cell death/survival, and cytokine production. The signaling pair has been implicated in hematopoietic malignancies and inflammatory disease, and a chemotherapy-CD30 antibody combination for the treatment of Hodgkin and other lymphomas has been developed. There are two recorded isoforms of CD30 ligand. All hitherto studies of CD30 ligand are of the first, canonical isoform, while the second isoform has never been described. This study aims to elucidate the properties and signaling functions of the second CD30 ligand isoform. We have found mRNA expression of both isoforms in the PBMCs of all six healthy donors tested. Through methods in cell biology and biochemistry, we were able to discover that the second CD30 ligand isoform has no discernable pro-inflammatory function and, in fact, isoform 2 can restrict the capacity of the canonical isoform to signal through the CD30 receptor by preventing their interaction. This discovery has implications for the future development of therapeutics targeting the CD30/CD30 ligand signaling pair in cancer and inflammatory disease.

The IRE1α Endonuclease Plays a Dual Role in Regulating the XBP1/miRNA-34a Axis and PD-1 Expression within Natural Killer Cells in Hodgkin Lymphoma

Plain Language SummaryNatural killer (NK) cells play a critical role in our innate immune defense against tumors without prior exposure to cancer cells and, therefore, make an attractive instrument to harness antitumoral immunity as novel immunotherapies. Hodgkin lymphoma (HL) typically lacks major histocompatibility complex class I which is a requirement for an antigen-specific recognition of effector T cells but not for the NK cell antitumoral function. NK cells are dysfunctional in HL patients mainly due to upregulation of immune checkpoint PD-1 expression that inhibits immune cells effector functions. However, the mechanisms underpinning PD-1 expression and NK cell dysfunction remain unknown. In this study, we uncovered the mechanism by which immune checkpoint PD-1 expression is upregulated upon activation of the endonuclease IRE1α to rapidly change the abundance of key regulatory molecules including a small noncoding regulatory RNA (microRNA-34a) and the transcription factor XBP1. The IRE1α endonuclease plays a dual role in regulating the XBP1/miRNA-34a axis and PD-1 expression within NK cells, which is disrupted in patients with HL. IRE1α pathway in NK cells represents a potential target to optimize NK cell immune functions in future HL treatments.