P063: Trial in Progress: Individualized Immunotherapy in Early-Stage Unfavorable Hodgkin Lymphoma - The Investigator-Initiated Phase II GHSG INDIE Trial
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SUBMITTER: Brockelmann P
PROVIDER: S-EPMC9621519 | biostudies-literature | 2022 Oct
REPOSITORIES: biostudies-literature
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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:Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell's palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.
| S-EPMC7955404 | biostudies-literature
Project description:ImportanceTo our knowledge, this is the first clinical trial designed to investigate concurrent treatment with a checkpoint inhibitor and conventional chemotherapy in relapsed or refractory classic Hodgkin lymphoma in patients destined for an autologous stem cell transplant.ObjectiveTo evaluate the complete response rate as assessed by 18F-fluorodeoxyglucose-positron emission tomography with computed tomography (FDG-PET/CT) after salvage therapy for patients with relapsed or refractory classic Hodgkin lymphoma.Design, setting, and participantsA single-group, phase 2, multi-institutional nonrandomized clinical trial to evaluate the addition of pembrolizumab to ifosfamide, carboplatin, and etoposide (ICE) chemotherapy was conducted from April 20, 2017, to October 29, 2020, at 5 US sites. The 42 patients were aged 18 years or older, with an Eastern Cooperative Oncology Group Performance Status Scale score of 0 or 1 and biopsy-proven relapsed or refractory classic Hodgkin lymphoma after 1 or 2 prior lines of chemotherapy. Patients were required to be appropriate candidates for transplant, with measurable lesions detected by FDG-PET/CT.InterventionsTwo cycles of pembrolizumab (200 mg intravenously on day 1) with ICE chemotherapy every 21 days, followed by stem cell mobilization and collection, and then 1 cycle of pembrolizumab monotherapy followed by FDG-PET/CT response assessment.Main outcomes and measuresThe primary end point was complete response rate detected by FDG-PET/CT, defined as a Deauville score of 3 or lower. Patients with a complete response proceeded to an autologous stem cell transplant. Secondary end points included progression-free survival, overall survival, stem cell mobilization, and neutrophil and platelet engraftment. Adverse events were monitored to assess safety.ResultsForty-two patients were enrolled, with 37 evaluable for the primary end point. The median age was 34 years (range, 19-70 years), 25 patients were female (68%), 6 were African American (16%), and 26 were White (70%). The complete response rate for the 37 patients assessed by FDG-PET/CT imaging was 86.5% (95% CI, 71.2%-95.5%); the overall response rate was 97.3% (36 patients), with 10.8% partial responses (4 patients). New areas of FDG-PET positivity in 2 patients were biopsied, showing noncaseating granuloma in 1 case and a reactive lymph node in a second. Progression-free survival and overall survival 2-year estimates were 87.2% (32 patients; 95% CI, 77.3%-98.3%) and 95.1% (95% CI, 88.8%-100%), respectively. The addition of pembrolizumab to ICE chemotherapy did not negatively affect stem cell mobilization or collection or engraftment, similar to prior experience in this patient population and setting.Conclusions and relevanceResults suggest that the addition of pembrolizumab to ICE chemotherapy was well tolerated and highly effective in comparison with prior reports of chemotherapy-only regimens, supporting further investigation in patients with relapsed or refractory classic Hodgkin lymphoma eligible for an autologous stem cell transplant.Trial registrationClinicalTrials.gov Identifier: NCT03077828.
| S-EPMC10020934 | biostudies-literature
Project description:This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.
| S-EPMC5025897 | biostudies-literature
Project description:IntroductionThe German Hodgkin Study Group (GHSG) HD17 trial established the omission of radiotherapy (RT) for patients with early-stage unfavorable Hodgkin lymphoma being PET-negative after 2 cycles of BEACOPP escalated plus 2 cycles of ABVD. This patient group reveals heterogeneity in characteristics and disease extent which prompted us to perform a decisive dosimetric analysis according to GHSG risk factors. This may help to tailor RT individually balancing risks and benefits.MethodsFor quality assurance, RT-plans were requested from the treating facilities (n= 141) and analyzed centrally. Dose-volume histograms were scanned either paper-based or digitally to obtain doses to mediastinal organs. These were registered and compared according to GHSG risk factors.ResultsOverall, RT plans of 176 patients were requested, 139 of which had dosimetric information on target volumes within the mediastinum. Most of these patients were stage II (92.8%), had no B-symptoms (79.1%) and were aged < 50 years (89.9%). Risk factors were present in 8.6% (extranodal involvement), 31.7% (bulky disease), 46.0% (elevated erythrocyte sedimentation rate) and 64.0% (three involved areas), respectively. The presence of bulky disease significantly affected the mean RT doses to the heart (p=0.005) and to the left lung (median: 11.3 Gy vs. 9.9 Gy; p=0.042) as well as V5 of the right and left lung, respectively (median right lung: 67.4% vs. 51.0%; p=0.011; median left lung: 65.9% vs. 54.2%; p=0.008). Significant differences in similar organs at risk parameters could be found between the sub-cohorts with the presence or absence of extranodal involvement, respectively. In contrast, an elevated erythrocyte sedimentation rate did not deteriorate dosimetry significantly. No association of any risk factor with radiation doses to the female breast was found.ConclusionPre-chemotherapy risk factors may help to predict potential RT exposure to normal organs and to critically review treatment indication. Individualized risk-benefit evaluations for patients with HL in early-stage unfavorable disease are mandatory.
| S-EPMC10196378 | biostudies-literature
Project description:Hodgkin lymphoma (HL) is a rare type of B-cell malignancy with bimodal age distribution targeting young adults and elderly. Prognostic models are available to identify risk of recurrence and response to treatment. Currently, positron emission tomography scanning is most useful in optimizing therapy. Outcomes are generally excellent with standard chemotherapy or combined modality therapy. Balancing efficacy and the risk of late effects in Hodgkin lymphoma is essential, including early detection of potential complications. Incorporation of novel therapies such as brentuximab vedotin and checkpoint inhibitors are being explored in the frontline setting, having already demonstrated improved survival and tolerable toxicity in advanced HL. Furthermore, the addition of these agents have the potential to transform treatment paradigms for early-stage HL and may result in improved outcomes with decreased risks of late toxicities that continue to afflict long-term survivors. However, the patient population, sequencing, and combinations with cytotoxic chemotherapy all remain still standing questions as results of current and upcoming randomized trials are awaited. In this article, we discuss the current data on the approach to initial treatment of early-stage classical HL, review toxicity profiles, and examine upcoming novel therapy trials.
| S-EPMC10905319 | biostudies-literature
Project description: Not available
| S-EPMC4288739 | biostudies-literature
Project description:The interaction between cluster of differentiation 47 (CD47) and signal regulatory protein α (SIRPα) protects healthy cells from macrophage attack, which is crucial for maintaining immune homeostasis. Overexpression of CD47 occurs widely across various tumor cell types and transmits the "don't eat me" signal to macrophages to avoid phagocytosis through binding to SIRPα. Blockade of the CD47-SIRPα axis is therefore a promising approach for cancer treatment. Lymphoma is the most common hematological malignancy and is an area of unmet clinical need. This review mainly described the current strategies targeting the CD47-SIRPα axis, including antibodies, SIRPα Fc fusion proteins, small molecule inhibitors, and peptides both in preclinical studies and clinical trials with Hodgkin lymphoma and non-Hodgkin lymphoma.
| S-EPMC10425755 | biostudies-literature
Project description:More than 80% of patients with advanced-stage Hodgkin lymphoma are now cured with contemporary treatment approaches. The ongoing challenge is how to further improve outcomes by identifying both high-risk patients who may benefit from more intensive frontline therapy to reduce the risk of relapse as well as lower-risk patients who may do just as well with less intensive therapy. Numerous trials have used an interim positron emission tomography (PET) response-adapted approach to evaluate early escalation or deescalation of therapy for patients with a positive or negative interim PET scan, respectively. Recent trials have incorporated novel agents, including brentuximab vedotin (BV) and the immune checkpoint inhibitors, in the frontline setting. Based on results of the ECHELON-1 trial, the Food and Drug Administration approved BV in combination with adriamycin, vinblastine, and dacarbazine chemotherapy for stage III to IV Hodgkin lymphoma. Improved methods to assess higher risk at diagnosis using quantitative PET metrics, such as metabolic tumor volume and total lesion glycolysis, and incorporation of emerging biomarkers may further refine patient selection for more intensive upfront therapy. The ultimate goal is to achieve the highest level of efficacy for an individual patient while minimizing the short- and long-term toxicities.
| S-EPMC6245987 | biostudies-literature
Project description:Although classical Hodgkin lymphoma (cHL) is usually curable, 20-30% of the patients experience treatment failure and most of them are typically treated with salvage chemotherapy and autologous stem cell transplantation (autoSCT). However, 45-55% of that subset further relapse or progress despite intensive treatment. At the advanced stage of the disease course, recently developed immunotherapeutic approaches have provided very promising results with prolonged remissions or disease stabilization in many patients. Brentuximab vedotin (BV) has been approved for patients with relapsed/refractory cHL (rr-cHL) who have failed autoSCT, as a consolidation after autoSCT in high-risk patients, as well as for patients who are ineligible for autoSCT or multiagent chemotherapy who have failed ≥ two treatment lines. However, except of the consolidation setting, 90-95% of the patients will progress and require further treatment. In this clinical setting, immune checkpoint inhibitors (CPIs) have produced impressive results. Both nivolumab and pembrolizumab have been approved for rr-cHL after autoSCT and BV failure, while pembrolizumab has also been licensed for transplant ineligible patients after BV failure. Other CPIs, sintilimab and tislelizumab, have been successfully tested in China, albeit in less heavily pretreated populations. Recent data suggest that the efficacy of CPIs may be augmented by hypomethylating agents, such as decitabine. As a result of their success in heavily pretreated disease, BV and CPIs are moving to earlier lines of treatment. BV was recently licensed by the FDA for the first-line treatment of stage III/IV Hodgkin lymphoma (HL) in combination with AVD (only stage IV according to the European Medicines Agency (EMA)). CPIs are currently being evaluated in combination with AVD in phase II trials of first-line treatment. The impact of BV and CPIs was also investigated in the setting of second-line salvage therapy. Finally, combinations of targeted therapies are under evaluation. Based on these exciting results, it appears reasonable to predict that an improvement in survival and a potential increase in the cure rates of cHL will soon become evident.
| S-EPMC6721364 | biostudies-literature