The Effect of Diagnostic and Therapeutic Changes on the Survival of Hodgkin's Lymphoma Patients (1980-2019).

Background and Objectives: The overall- and progression-free survival rates of Hodgkin's lymphoma patients have improved. Our goal was to examine the changes in our treatment results and their causes depending on the daily diagnostic and therapeutic practice. Materials and Methods: We analysed data of 776 classical Hodgkin lymphoma patients treated between 1980 and 2019. Patient data were investigated in ten-year periods (first period: 1980-1989, second period: 1990-1999, third period: 2000-2009, and fourth period: 2010-2019). Results: Radiotherapy alone as a first-line treatment was used progressively less often, and in the 4th period it was no longer used before or without chemotherapy. The use of combined chemo- and radiotherapy decreased in the last period, and the number of those patients who received only chemotherapy increased significantly. The 10-year overall survival improved significantly from 1990 to 1999 compared to 2010 to 2019 (74.9% vs. 86.9%). About 30% of patients relapsed after or were refractory to first-line therapy in each period. The incidence of relapse in the last period did not increase after two years, but there was no significant difference between the periods. Conclusions: Overall survival rates of HL patients have improved significantly in recent decades, which is due to improved diagnostic methods and modern therapies. Progression-free survival is unchanged; one-third of patients relapse or are refractory to first-line treatment within the first two years. Early recognition of R/R patients, the early application of newer and already available innovative therapies, and the finding of additional new and effective therapies are of particular importance.

Efficacy of escalating therapy with brentuximab vedotin-AVD in advanced stage Hodgkin lymphoma patients with positive interim positron emission tomography after ABVD.

Patients with advanced-stage Hodgkin lymphoma treated with ABVD who have a positive interim FDG-PET (iPET) have a poor prognosis. Escalation to BEACOPP has been shown to improve progression-free survival (PFS). However, randomized trials are lacking to determine the best strategy for intensification. We report on A-AVD escalation treatment outcomes for 15 iPET-positive patients post-ABVD. Overall response and complete response rates were 80% and 60%, respectively. Four patients underwent salvage therapy followed by autologous stem cell transplantation. At a median 17-month follow-up, all patients are alive, 87% in complete remission, and 1-year PFS was 57.8%. For patients ineligible for BEACOPP due to age, comorbidities, or preference, A-AVD escalation may be a viable alternative.

The role of autologous stem-cell transplantation in classical Hodgkin lymphoma in the modern era.

Despite excellent cure rates with modern front-line regimens, up to 20% of patients with Hodgkin lymphoma will progress through front-line therapy or experience disease relapse. Worldwide, salvage chemotherapy followed by high-dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) is considered the standard of care for these patients and can cure approximately 50% of relapsed or refractory (R/R) patients in the second line. Brentuximab vedotin (BV), an anti-CD30 antibody drug conjugate, and PD1 inhibitors like nivolumab and pembrolizumab, have high response rates in patients who recur after HDT/ASCT. When used prior to HDT/ASCT, BV and PD1 inhibitors appear to dramatically increase the effectiveness of salvage therapies with complete response rates often double those seen with historic chemotherapy-based regimens and durable progression free survival (PFS) post-HDT/ASCT. Emerging data in adults and from pediatric trials showing a durable PFS in a subset of relapsed patients raises the question of whether HDT/ASCT is essential for cure in R/R patients after PD1 based salvage. Future studies will help clarify if ASCT can omitted PD1 based salvage to avoid the potential toxicity of HDT/ASCT without compromising cure.

Hodgkin lymphoma involving the extra-axial CNS: an AHOD1331, PHL-C1, and PHL-C2 report from the COG and EuroNet-PHL.

ABSTRACT: Hodgkin lymphoma (HL) involving the central nervous system (CNS) is exceedingly rare. Information regarding the presentation, management, treatment, and outcome of patients with CNS HL is limited to case reports or small series. We describe 45 pediatric patients with 55 extra-axial CNS lesions at diagnosis with HL from a cohort of 4995 patients enrolled on Children's Oncology Group AHOD1331 and the European Network for Pediatric Hodgkin lymphoma C1 and C2 trials, with an overall incidence of 0.9%. Up to 82.2% of patients had a single CNS lesion in the thoracic, lumbar, or sacral spine. In the evaluated cohort, HL did not occur within the CNS parenchyma. Lesions extended into the extra-axial CNS space from adjacent soft tissue or bone and never directly infiltrated through the dura into the brain or spinal cord. Patients with CNS involvement had a twofold greater incidence of extranodal lesions than previously reported cohorts without CNS involvement. After 2 cycles of chemotherapy, 89.1% of CNS lesions demonstrated a complete metabolic response and >75% decrease in volume. Thirteen CNS lesions (23.6%) received irradiation; none were sites of disease relapse. Relapse occurred at the site of 2 lesions involving the CNS, both of which had an adequate interim response to chemotherapy. In summary, we present, to our knowledge, the largest reported cohort of systemic HL involving the CNS at diagnosis, demonstrating that these lesions originate from surrounding tissues, extend into the extra-axial CNS space, and respond similarly to other nodal and extranodal disease. The trials were registered at www.clinicaltrials.gov as #NCT02166463, #NCT00433459, and #NCT02684708.

Cisplatin as a Viable and Secure Alternative to Carmustine in BEAM-Based Conditioning for Autologous Hematopoietic Stem Cell Transplantation in Patients with Lymphoma.

BACKGROUND: High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is a standard treatment for relapsed/refractory lymphoma patients. Yet, the widespread use of BEAM is hindered by carmustine accessibility. This study evaluates the efficacy and safety of PEAM (Cisplatin, Etoposide, Cytarabine, and Melphalan) versus BEAM in auto-HSCT for Hodgkin (HL) and non-Hodgkin lymphoma (NHL) patients. METHODS: We conducted a retrospective single-center study of adult lymphoma patients who received PEAM or BEAM pretransplant conditioning between January 2004 to December 2022, comparing efficacy and safety outcomes. RESULTS: Among 143 patients (median age of 33 years, 58% males), 55 had HL, and 88 had NHL. The overall response rate (ORR) was 86.7% for PEAM and 72.3% for BEAM, and the relapse rate (RR) was lower for PEAM than BEAM (22.9% vs 45.6%). Median time to relapse (TTR) and overall survival (OS) were not reached for either group. PEAM exhibited a shorter time to both neutrophil (NE) and platelet (PE) engraftment compared to BEAM (10 vs 12 days), with a more tolerable gastrointestinal (GI) toxicity profile. CONCLUSIONS: Both BEAM and PEAM showed similar outcomes, demonstrating comparable efficacy in terms of ORR, TTR, and OS for both HL and NHL patients. However, PEAM-conditioning was associated with a shorter time to engraftment and fewer GI adverse events.

Treatment approaches for older Hodgkin lymphoma patients.

PURPOSE OF REVIEW: Hodgkin lymphoma (HL) occurs at two age peaks around 25 and 60 years of age. Due to varying fitness and co-morbidities older patients are a heterogeneous group that has relatively poor treatment outcomes. The evolving therapeutic landscape for older HL is summarized herein. RECENT FINDINGS: Due to lack of data from larger trials and approval of novel drugs, first-line treatment of limited-stage HL (i.e. early-stage favourable and unfavourable) remains largely A(B)VD and radiotherapy based. For patients with advanced-stage HL, the anti-CD30 antibody-drug conjugate brentuximab vedotin is approved in combination with AVD chemotherapy (BV-AVD). Due to toxicities such as febrile neutropenia or polyneuropathy and lack of improvement in progression-free and overall survival in the older subgroup, fully concomitant BV-AVD is however not used widely. More recently, promising early data was reported with the combination of nivolumab and AVD (N-AVD) in patients >60 years with advanced-stage HL. Second-line treatment depends on fitness and might include high-dose chemotherapy and autologous stem-cell transplantation for selected patients. For unfit or multiply relapsed patients, anti-PD1 antibodies are the preferred treatment option. SUMMARY: The increasing number of older HL patients constitutes a therapeutic challenge despite recent advances and the increased usage of targeted agents.

What is the best salvage therapy for Hodgkin lymphoma?

PURPOSE OF REVIEW: Historically, salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (HDT/ASCT) was the mainstay approach for relapsed or refractory classic HL. The emergence of novel agents for HL, such as brentuximab vedotin and programmed death-1 (PD-1) blockade has revolutionized therapeutic strategies, yielding excellent results. This review aims to provide a comprehensive overview of new salvage therapies and offer insights into forthcoming therapeutic options. RECENT FINDINGS: The incorporation of brentuximab vedotin and PD-1 blockade into salvage therapy before HDT/ASCT has led to markedly improved outcomes. Notably, PD-1 based salvage studies yield posttransplant 2-year progression-free survival rates approaching 90%, marking a significant advancement in the treatment of Hodgkin lymphoma (HL). Studies are beginning to explore nontransplant treatment approaches following front-line treatment failure and may identify certain risk groups eligible for these strategies. SUMMARY: The landscape of HL treatment is rapidly evolving, leading to significant changes in the standard of care. Novel agents are now administered earlier in the disease course, resulting in higher cure rates. The focus of treatment is shifting towards achieving cure with minimal toxicity, reducing exposure to various agents, and advancing research in optimizing treatment sequencing and patient selection for less intensive therapies.

How to treat localized Hodgkin lymphoma?

PURPOSE OF REVIEW: We aim to summarize the current knowledge on the management of early-stage classical Hodgkin lymphoma, with a focus on conventional strategies, incorporation of immunotherapies and exploration of novel prognostic markers. RECENT FINDINGS: Long-term data on combined modalities (associating chemotherapy and radiotherapy) still supports their benefit in terms of progression free survival compared to chemotherapy alone in both early favourable and early unfavourable interim PET-negative classical Hodgkin Lymphoma. Novel agents, such as Brentuximab Vedotin and checkpoints inhibitors show promising and impressive results when added to first-line treatment. Various strategies have been used, mainly in phase 2 non randomized clinical trials. Interim PET-scan has limited prognostic value and its role in regimens incorporating immunotherapies is yet unknown. Other prognosis markers emerge, such as metabolic tumour volume and circulating tumour DNA. By reflecting tumour burden pretreatment and minimal residual disease on treatment, they might be useful tools guiding treatment decisions. SUMMARY: Novel immunotherapy agents are likely to change the landscape in front-line management of classical early-stage Hodgkin lymphoma by combined modality treatment. Despite encouraging recent data, proof of their efficacy and safety on the longer term are still needed. Treatment decisions might be guided by new promising prognosis markers but their use in clinical practice is still to be determined.

Survivorship after Hodgkin lymphoma and the right to be forgotten.

PURPOSE OF REVIEW: The significantly improved survivorship in Hodgkin lymphoma is fraught with challenges, including persistent symptoms, secondary health complications, and socio-professional obstacles. This review highlights the need for comprehensive survivorship care plans that include detection of relapse, assessment of long-term side effects, screening for secondary cancers, psychological support, and assistance with socio-professional integration. RECENT FINDINGS: Cardiovascular diseases, secondary malignancies and other associated risks remains an important problem related to the effective treatment of patients with Hodgkin lymphoma. Furthermore, fertility concerns and endocrine disorders remain prevalent issues posttreatment. An optimal evaluation of the risks before and after treatment is essential to reduce the impact of these side effects on quality of life. Addressing the socio-professional reintegration of survivors, the concept of the 'Right to be forgotten' emerges as a critical consideration. This principle seeks to eliminate discrimination against cancer survivors in accessing financial services and aims for legislative changes to ensure that past cancer diagnosis does not unfairly affect survivors' futures. Implementation of this 'Right to be forgotten' in the legislature, is currently underway in European countries. SUMMARY: The focus of survivorship care has shifted towards the holistic management of these long-term outcomes. Quality of life for Hodgkin lymphoma survivors is affected by various treatment-related factors, with evidence suggesting that physical, psychological and socio-professional domains remain impacted years after treatment.

The pediatric approach to Hodgkin lymphoma.

Hodgkin lymphoma (HL) occurs throughout the lifespan but is one of the most common cancers in adolescents and young adults (AYA; 15-39 years). HL has become a highly curable disease with survival rates surpassing 90%, including patients with high-risk and advanced stage disease. Unfortunately, intensive treatment carries a risk of short- and long-term toxicity. Given the decades pediatric HL survivors are expected to live after treatment, the pediatric approach to treatment has focused on improving the therapeutic index through response adapted treatment and more recently the incorporation of novel agents. The efforts of pediatric and medical oncologists in research and clinical trial development have long occurred in parallel, but recent efforts have laid the foundation for collaboration with the goal of standardizing AYA care and allowing earlier incorporation of novel therapy for younger patients. This review focuses on the evolution of the management of pediatric HL including epidemiology, biology, and approaches to upfront and salvage treatment regimens.

Autologous Peripheral Blood Stem Cell Transplantation and Timing of Local Radiation Therapy in Patients With Malignant Lymphoma: Results of the Japanese Radiation Oncology Study Group Questionnaire Survey.

BACKGROUND/AIM: Malignant lymphoma (ML) including Hodgkin's lymphoma and non-Hodgkin's lymphoma is often treated with local radiation therapy (RT) in combination with autologous hematopoietic stem cell transplantation (ASCT) to prevent relapse; however, the efficacy and optimal timing of this approach is unclear. In this study, a national survey conducted by the Japanese Radiation Oncology Study Group reviewed ML cases from 2011 to 2019 to determine whether RT should be added to ASCT, focusing on the use of autologous peripheral blood stem cell transplantation (auto-PBSCT), a predominant form of ASCT. PATIENTS AND METHODS: The survey encompassed 92 patients from 11 institutes, and assessed histological ML types, treatment regimens, timing of RT relative to auto-PBSCT, and associated adverse events. RESULTS: The results indicated no significant differences in adverse events, including myelosuppression, based on the timing of RT in relation to auto-PBSCT. However, anemia was more prevalent when RT was administered before auto-PBSCT, and there was a higher incidence of neutropenia recovery delay in patients receiving RT after auto-PBSCT. CONCLUSION: This study provides valuable insights into the variable practices of auto-PBSCT and local RT in ML treatment, emphasizing the need for optimized timing of these therapies to improve patient outcomes and reduce complications.

Clinical Features and Therapeutic Outcomes Comparing Primary Mediastinal Large B-cell Lymphoma to Mediastinal Hodgkin Disease.

Currently, there is limited data available comparing Primary Mediastinal Large B-cell Lymphoma (PMBL) and mediastinal Hodgkin disease, nodular sclerosis type (HDNS). This is a retrospective cohort study that compares the clinical features, histology through immunohistochemistry (IHC) and treatment outcomes of 19 cases of PMBL and 39 cases of HDNS diagnosed over 13 years at a single institution in San Juan, PR. Superior Vena Cava syndrome (SVCS) and elevated Lactate Dehydrogenase (LDH) levels were more frequently seen in the PMBL cohort. At the median follow-up visit, of 74 months, no significant difference was seen in overall survival or progression free survival between PMBL and HDNS. Almost all of the relapses in the PMBL group occurred within 12 months of diagnosis. Our data suggests that PMBL and HDNS differ in their clinical presentation and have a favorable prognosis.

Characterizing Chemotherapy/Radiotherapy-Induced Genome Chaos in Hodgkin's Lymphoma Patients Using M-FISH.

Hodgkin lymphoma (HL) is one of the most common lymphomas, with an incidence of 3 per 100,000 persons. Current treatment uses a cocktail of genotoxic agents, including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD), along with or without radiotherapy. This treatment regimen has proved to be efficient in killing cancer cells, resulting in HL patients having a survival rate of >90% cancer-free survival at five years. However, this therapy does not have a specific cell target, and it can induce damage in the genome of non-cancerous cells. Previous studies have shown that HL survivors often exhibit karyotypes characterized by complex chromosomal abnormalities that are difficult to analyze by conventional banding. Multicolor fluorescence in situ hybridization (M-FISH) is a powerful tool to analyze complex karyotypes; we used M-FISH to investigate the presence of chromosomal damage in peripheral blood lymphocytes from five healthy individuals and five HL patients before, during, and one year after anti-cancer treatment. Our results show that this anti-cancer treatment-induced genomic chaos that persists in the hematopoietic stem cells from HL patients one year after finishing therapy. This chromosomal instability may play a role in the occurrence of second primary cancers that are observed in 10% of HL survivors. This chapter will describe a protocol for utilizing M-FISH to study treatment-induced genome chaos in Hodgkin's lymphoma (HL) patients, following a brief discussion.

JAK inhibition enhances checkpoint blockade immunotherapy in patients with Hodgkin lymphoma.

Unleashing antitumor T cell activity by checkpoint inhibitor immunotherapy is effective in cancer patients, but clinical responses are limited. Cytokine signaling through the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway correlates with checkpoint immunotherapy resistance. We report a phase I clinical trial of the JAK inhibitor ruxolitinib with anti-PD-1 antibody nivolumab in Hodgkin lymphoma patients relapsed or refractory following checkpoint inhibitor immunotherapy. The combination yielded a best overall response rate of 53% (10/19). Ruxolitinib significantly reduced neutrophil-to-lymphocyte ratios and percentages of myeloid suppressor cells but increased numbers of cytokine-producing T cells. Ruxolitinib rescued the function of exhausted T cells and enhanced the efficacy of immune checkpoint blockade in preclinical solid tumor and lymphoma models. This synergy was characterized by a switch from suppressive to immunostimulatory myeloid cells, which enhanced T cell division.

Optimizing salvage therapy for Hodgkin lymphoma: progress and future challenges.

INTRODUCTION: Despite clear advancements in the management of classical Hodgkin lymphoma (cHL) over the past decade including better risk stratification, the usage of 18F-flurodeoxyglucose positron emission tomography (FDG-PET)-guided approaches and incorporation of novel agents, approximately one-third of the patients will relapse. Important themes have been recently explored in the first salvage setting including the recognition of the positive prognostic value of a negative pre-autologous stem cell transplantation (ASCT) FDG-PET response and the incorporation of novel agents such as brentuximab vedotin (BV) and immune checkpoint inhibitors (CPIs) as salvage regimens to improve patient outcomes. AREAS COVERED: The evolving treatment paradigm in optimizing salvage therapy in relapsed refractory cHL (RR-cHL) is discussed, including a vision to the future. The methodology included a literature search on PubMed using keywords. Selected articles were screened and evaluated by the authors of this review. EXPERT OPINION: Achieving a complete remission by FDG-PET pre-ASCT is the most important prognostic factor in obtaining disease control and subsequent cure, and therefore should be a key goal of any salvage regimen. Although data from randomized controlled trials are currently lacking, retrospective evidence demonstrate superior event free survival with CPI-based regimens compared to conventional chemotherapy or BV-based therapy.

[Current Standards in the Treatment of Hodgkin Lymphoma]. / Aktuelle Standards in der Behandlung des Hodgkin Lymphoms.

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.

A systematic literature review of clinical evidence and treatment burden in newly diagnosed high-risk pediatric patients with classical Hodgkin lymphoma.

This systematic literature review evaluated frontline treatment burden in pediatric and adolescent/young adult (AYA) patients with high-risk classical Hodgkin lymphoma (cHL) among studies originating from the United States. Data were extracted from 32 publications (screened: total, n = 3115; full-text, n = 98) representing 12 studies (randomized controlled trials [RCTs], n = 2; non-comparative, non-randomized, n = 7; observational, n = 3). High-risk disease definitions varied across studies. Five-year event-free survival (EFS)/progression-free survival (PFS) was 86%-100% and 79%-94%, and complete response rates were 35%-100% and 5%-64% for brentuximab vedotin (BV)-containing and chemotherapy-alone regimens, respectively. In identified RCTs, BV-containing compared with chemotherapy-alone regimens demonstrated significantly longer 3-year EFS/5-year PFS. Hematological and peripheral neuropathy were the most commonly reported adverse events of interest, although safety data were inconsistently reported. Few studies evaluated humanistic and no studies evaluated economic burden. Results from studies with the highest quality of evidence indicate an EFS/PFS benefit for frontline BV-containing versus chemotherapy-alone regimens for pediatric/AYA patients with high-risk cHL.