T002: Treatment related morbidity in patients with classical Hodgkin Lymphoma: results of the ongoing, randomized phase III HD21 Trial by The German Hodgkin Study Group
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SUBMITTER: Borchmann P
PROVIDER: S-EPMC9621550 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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| S-EPMC8807388 | biostudies-literature
Project description:The 9p24.1 chromosomal alteration in classical Hodgkin lymphoma (cHL) is associated with increased expression of programmed death ligand 1 (PD-L1)/PD-L2 and an immunosuppressive tumor microenvironment. Blockade of PD-L1/PD-1 interactions with avelumab (anti-PD-L1) is hypothesized to restore antitumor immunity. JAVELIN Hodgkins was a phase 1b, multiple-dose, open-label, randomized, parallel-arm trial of avelumab in patients with relapsed/refractory (R/R) cHL. Primary end points included avelumab target occupancy by dose/schedule in peripheral blood immune cells and pharmacokinetic parameters. Secondary end points included safety and antitumor activity. Four dose levels and 2 dosing schedules were investigated: 70, 350, and 500 mg administered every 2 weeks; 500 mg every 3 weeks; and 10 mg/kg every 2 weeks. Thirty-one patients with R/R cHL were randomized; 9 (29.0%) and 20 (64.5%) had received 3 or ≥4 prior anticancer treatments, respectively. Target occupancy of >90% was observed across all treatment arms, throughout the dosing interval. Avelumab pharmacokinetic data were similar to those previously reported. The most common treatment-related adverse events of any grade were infusion-related reaction (30.0%), nausea (20.0%), increased alanine aminotransferase and rash (16.7% each), and fatigue (13.3%). The objective response rate (ORR) in all randomized patients was 41.9%, with a complete response rate of 19.4%; ORR in those with prior allogeneic hematopoietic stem cell transplant (allo-HSCT) was 55.6%. Due to decreased use of allo-HSCT in patients with R/R cHL, the expansion phase enrolling post-allo-HSCT patients was terminated. Avelumab was tolerable and demonstrated antitumor activity in heavily pretreated patients with cHL, suggesting that PD-L1 blockade may be sufficient for therapeutic benefit in cHL. This trial was registered at www.clinicaltrials.gov as #NCT02603419.
| S-EPMC8525219 | biostudies-literature
Project description:In classical Hodgkin lymphoma, circulating clonotypic malignant cells express CD20, which potentially explains the observed activity of rituximab. This multicenter phase 2 study investigated the combination of rituximab-ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) for stage II-IV untreated classical Hodgkin lymphoma. A goal was to assess the behavior of circulating clonotypic B cells clinically. Of 49 evaluable patients, 69% had stage IIB-IV disease; 8% had CD20(+) Hodgkin and Reed-Sternberg cells. Rituximab-ABVD was generally well tolerated. Delivered relative dose intensity was 94% for AVD and 79% for bleomycin. After 6 cycles, 81% of patients were in complete remission. Only 8% received radiation therapy. The actuarial 3-year event-free and overall survival rates were 83% and 98%, respectively. EBV copy number in plasma fell dramatically during cycle 1 in patients with EBV(+) tumors. Persistence of detectable circulating clonotypic B cells was associated with a greater relapse frequency (P < .05). Rituximab-ABVD and clonotypic B cells warrant additional study in classical Hodgkin lymphoma.
| S-EPMC3359734 | biostudies-literature
Project description:ImportanceIn early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL.ObjectiveTo evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL.Design, setting, and participantsThis was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible.InterventionsSystemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy.Main outcomes and measuresComplete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group.ResultsOf 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy.Conclusions and relevanceBoth strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL.Trial registrationClinicalTrials.gov Identifier: NCT03004833.
| S-EPMC7193521 | biostudies-literature
Project description:BACKGROUND: Health-related quality of life (HRQoL) comprises different domains of physical, mental, and social well-being. In this analysis, we focus on sexual quality of life in Hodgkin Lymphoma (HL) patients. METHODS: Four-thousand one-hundred and sixty patients enroled in the HD10-HD12 trials underwent HRQoL assessment. Instruments included the Quality of Life Questionnaire for survivors (QLQ-S), combining the European Organisation for Research and Treatment of Cancer QLQ-C30, Multidimensional fatigue (FA) inventory (MFI-20) and an additional sexual functioning (SX) scale. We describe SX up to 27 months after therapy and analyse relationship to stage, age, gender, FA, social functioning, and therapy. Statistical methods range from descriptive statistics to a classification of SX courses, and a longitudinal structural equations model with full information maximum likelihood estimation of missing data. In the analysis, a score below 50 was used to describe severe sexual dysfunction. RESULTS: Three-thousand two-hundred and eight patients provided data on SX. Patients in advanced stages reported lower SX than patients in early stages both, before and after the treatment. During follow-up, an improvement of SX compared with baseline was detected, except for those ≥50 years. Patients in early stages reached normal SX, whereas advanced-stage patients remained below the reference value for healthy controls. Sexual functioning during follow-up was significantly and strongly related to previous SX, other HRQoL measures, age, and stage, and to lesser degree with gender and chemotherapy. CONCLUSION: Overall, HL patients have a decreased sexual quality of life at baseline, which improves after therapy and normalises in early-stage patients. Importantly, long-term SX is more closely related to patient characteristics and SX at baseline than to the intensity of treatment.
| S-EPMC3553532 | biostudies-other
Project description:Background:The current standard of care for classical Hodgkin lymphoma (HL) is multiagent chemotherapy with or without radiation. In patients who relapse or fail to respond, additional high-dose chemotherapy with autologous hematopoietic stem cell transplantation (AHSCT) can improve progression-free survival (PFS). Novel therapies are required for patients refractory to chemotherapy and AHSCT. The mammalian target of rapamycin inhibitor everolimus has shown preliminary activity in preclinical models of HL and promising efficacy in patients with relapsed or refractory HL. Methods:This was an open-label, two-stage, phase 2 study that enrolled 57 patients aged ??18 years with classic HL that had progressed after standard therapy. Patients received everolimus 10 mg daily until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision. The primary endpoint was overall response rate; secondary endpoints included PFS, overall survival, time to response, duration of response, and safety. Results:Overall response rate was 45.6% (95% confidence interval [CI] 32.4-59.3%); five patients (8.8%) experienced a complete response and 21 patients had a partial response (36.8%). Median PFS was 8.0 months (95% CI 5.1-11.0 months). Seven patients (12%) were long-term responders (??12 months). The most common study drug-related adverse events were thrombocytopenia (45.6%), fatigue (31.6%), anemia (26.3%), rash (24.6%), and stomatitis (22.8%). Conclusions:Everolimus 10 mg/day demonstrated favorable results in patients with heavily pretreated, relapsed, or refractory classical HL. These findings support the further evaluation of everolimus in this indication.Trial registration ClinicalTrials.gov NCT01022996. Registered November 25, 2009.
| S-EPMC5948762 | biostudies-literature
Project description:BackgroundMany patients with classical Hodgkin lymphoma show increased programmed death-1 ligand expression in Reed-Sternberg cells. We report the final results of a phase II study of nivolumab, an anti-programmed death-1 monoclonal antibody, in Japanese patients with relapsed or refractory classical Hodgkin lymphoma.MethodsJapanese patients with previously treated classical Hodgkin lymphoma (aged ≥ 20 years) were administered nivolumab (3 mg/kg on Day 1 of 14-day cycles) until progressive disease, an unacceptable adverse event, or another clinically relevant reason. Treatment could continue beyond progressive disease at the investigator's discretion in selected patients.ResultsSeventeen patients (median age: 63.0 years) were enrolled. The median follow-up was 38.8 months. One patient with non-Hodgkin lymphoma was excluded from efficacy analyses. The centrally assessed overall response rate in 16 classical Hodgkin lymphoma patients was 87.5% (95% confidence interval = 61.7-98.4%) and the disease control rate was 93.8% (95% confidence interval = 69.8-99.8%). The median (95% confidence interval) duration of response and progression-free survival were 8.5 (2.4-12.6) and 11.7 (1.8-42.3) months, respectively. The 3-year overall survival rate was 80.4% (95% confidence interval = 50.6-93.2%). Nivolumab was continued beyond progressive disease in seven patients; six were alive at the data cut-off. Adverse drug reactions occurred in all 17 patients with grades 3-4 adverse drug reactions in eight patients and no grade 5 adverse drug reactions. Pulmonary toxicities occurred in five patients; four of these occurred ≥17 months after starting nivolumab.ConclusionNivolumab is effective and tolerable in Japanese relapsed or refractory classical Hodgkin lymphoma patients. Continued monitoring may be necessary to detect late-onset pulmonary toxicities.Clinical trial registrationJapicCTI-142755 (Japan Pharmaceutical Information Center).
| S-EPMC7579338 | biostudies-literature
Project description:Classical Hodgkin lymphoma (cHL) is one of the most prevalent lymphomas with a unique cell composition compared to other lymphoma entities. Rare, malignant Hodgkin and Reed-Sternberg (HRS) cells embedded with an extensive but ineffective immune infiltration were previously characterized by a large number of genetic and epigenetic alterations. Recently, microRNA profiling studies highlighted the importance of small non-coding RNA in cHL. This review summarizes available literature data and provides a detailed comparison of four studies where cHL cell lines and microdissected HRS cells were used. Several microRNAs were found to be consistently up- (let-7-f, mir-9, mir-21, mir-23a, mir-27a, mir-155, and mir-196a) or downregulated (mir-138 and mir-150) in cHL. These deregulated microRNAs are involved in the processes crucial for cHL pathogenesis, such as impaired B cell development (mir-9, mir-150, and mir-155), NFκB hyperactivation (mir-155 and mir-196a), and immune evasion (mir-138). Therefore, the deregulation of microRNA expression can be considered a complementary mechanism to genetic alterations promoting lymphomagenesis. Moreover, the expression of let-7f, mir-9 and mir-27a is specific for cHL and can serve as a biomarker to distinguish this lymphoma from other B cell lymphomas. However, additional in-depth and high throughput analysis of microRNA expression in HRS cells is necessary to decipher the complete picture of microRNA in cHL.
| S-EPMC8032569 | biostudies-literature
Project description:This phase II trial was designed to determine the safety and efficacy of a modified paediatric risk-stratified protocol in young adults (18-30 years) with classical Hodgkin Lymphoma. The primary end-point was neurotoxicity rate. The incidence of grade 3 neurotoxicity was 11% (80% CI, 5-19%); a true rate of neuropathy of >15% cannot be excluded. Neuropathy and associated deterioration in quality of life was largely reversible. The overall response rate was 100% with 40% complete remission (CR) rate. Twelve months disease-free survival (DFS) was 91%. We demonstrate that a risk-stratified paediatric combined modality treatment approach can be delivered to young adults without significant irreversible neuropathy.
| S-EPMC7154553 | biostudies-literature
Project description:Hodgkin lymphoma is a haematological malignancy predominantly affecting young adults. Hodgkin lymphoma is a highly curable disease by current treatment standards. Latest treatment guidelines for Hodgkin lymphoma however imply access to diagnostic and treatment modalities that may not be available in settings with restricted healthcare resources. Considerable discrepancies in Hodgkin lymphoma patient survival exist, with poorer outcomes reported in resources-constrained settings. Resources-stratified guidelines for diagnosis, staging and treatment of Hodgkin lymphoma were derived in an effort to optimize patient outcome provided a given setting of available resources. These guidelines were derived based on the framework of the Breast Health Global Initiative stratifying resource levels in basic, core, advanced and maximal categories.
| S-EPMC7084688 | biostudies-literature