Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) for whom autologous hematopoietic cell transplantation (auto-HCT) had failed experienced frequent and durable responses to nivolumab in the phase 2 CheckMate 205 trial. We present updated results (median follow-up, ∼5 years). Patients with R/R cHL who were brentuximab vedotin (BV)-naive (cohort A), received BV after auto-HCT (cohort B), or received BV before and/or after auto-HCT (cohort C) were administered with nivolumab 3 mg/kg IV every 2 weeks until progression or unacceptable toxicity. Patients in cohort C with complete remission (CR) for 1 year could discontinue nivolumab and resume upon relapse. Among 243 patients (cohort A, n = 63; B, n = 80; and C, n = 100), the objective response rate (ORR) was 71.2% (95% confidence interval [CI], 65.1-76.8); the CR rate was 21.4% (95% CI, 16.4-27.1). Median duration of response, CR, and partial remission were 18.2 (95% CI, 14.7-26.1), 30.3, and 13.5 months, respectively. Median progression-free survival was 15.1 months (95% CI, 11.3-18.5). Median overall survival (OS) was not reached; OS at 5 years was 71.4% (95% CI, 64.8-77.1). In cohort C, all 3 patients who discontinued in CR and were subsequently re-treated achieved objective response. No new or unexpected safety signals were identified. This 5-year follow-up of CheckMate 205 demonstrated favorable OS and confirmed efficacy and safety of nivolumab in R/R cHL after auto-HCT failure. Results suggest patients may discontinue treatment after persistent CR and reinitiate upon progression. This trial was registered at www.clinicaltrials.gov as #NCT02181713.
- MeSH
- brentuximab vedotin MeSH
- chronická nemoc MeSH
- Hodgkinova nemoc * patologie MeSH
- imunokonjugáty * MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- nivolumab terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
PURPOSE: In the phase III CheckMate 238 study, adjuvant nivolumab significantly improved recurrence-free survival (RFS) and distant metastasis-free survival versus ipilimumab in patients with resected stage IIIB-C or stage IV melanoma, with benefit sustained at 4 years. We report updated 5-year efficacy and biomarker findings. PATIENTS AND METHODS: Patients with resected stage IIIB-C/IV melanoma were stratified by stage and baseline programmed death cell ligand 1 (PD-L1) expression and received nivolumab 3 mg/kg every 2 weeks or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks, both intravenously for 1 year until disease recurrence, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. RESULTS: At a minimum follow-up of 62 months, RFS with nivolumab remained superior to ipilimumab (HR = 0.72; 95% confidence interval, 0.60-0.86; 5-year rates of 50% vs. 39%). Five-year distant metastasis-free survival (DMFS) rates were 58% with nivolumab versus 51% with ipilimumab. Five-year overall survival (OS) rates were 76% with nivolumab and 72% with ipilimumab (75% data maturity: 228 of 302 planned events). Higher levels of tumor mutational burden (TMB), tumor PD-L1, intratumoral CD8+ T cells and IFNγ-associated gene expression signature, and lower levels of peripheral serum C-reactive protein were associated with improved RFS and OS with both nivolumab and ipilimumab, albeit with limited clinically meaningful predictive value. CONCLUSIONS: Nivolumab is a proven adjuvant treatment for resected melanoma at high risk of recurrence, with sustained, long-term improvement in RFS and DMFS compared with ipilimumab and high OS rates. Identification of additional biomarkers is needed to better predict treatment outcome. See related commentary by Augustin and Luke, p. 3253.
- MeSH
- adjuvancia imunologická terapeutické užití MeSH
- antigeny CD274 MeSH
- antigeny CD279 terapeutické užití MeSH
- biologické markery MeSH
- ipilimumab terapeutické užití MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- melanom * farmakoterapie genetika patologie MeSH
- nivolumab * aplikace a dávkování MeSH
- protokoly protinádorové kombinované chemoterapie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Data on stem cell transplantation (SCT) for Diamond-Blackfan Anemia (DBA) is limited. We studied patients transplanted for DBA and registered in the EBMT database. Between 1985 and 2016, 106 DBA patients (median age, 6.8 years) underwent hematopoietic stem cell transplantation from matched-sibling donors (57%), unrelated donors (36%), or other related donors (7%), using marrow (68%), peripheral blood stem cells (20%), both marrow and peripheral blood stem cells (1%), or cord blood (11%). The cumulative incidence of engraftment was 86% (80% to 93%), and neutrophil recovery and platelet recovery were achieved on day +18 (range, 16 to 20) and +36 (range, 32 to 43), respectively. Three-year overall survival and event-free survival were 84% (77% to 91%) and 81% (74% to 89%), respectively. Older patients were significantly more likely to die (hazard ratio, 1.4; 95% confidence interval, 1.06 to 1.23; P < .001). Outcomes were similar between sibling compared to unrelated-donor transplants. The incidence of acute grades II to IV of graft-versus-host disease (GVHD) was 30% (21% to 39%), and the incidence of extensive chronic GVHD was 15% (7% to 22%). This study shows that SCT may represent an alternative therapeutic option for transfusion-dependent younger patients.
Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.
- MeSH
- antigeny CD274 antagonisté a inhibitory biosyntéza genetika imunologie MeSH
- antigeny CD279 antagonisté a inhibitory biosyntéza genetika imunologie MeSH
- beta-2-mikroglobulin biosyntéza genetika imunologie MeSH
- buňky Reedové-Sternberga účinky léků imunologie patologie MeSH
- doba přežití bez progrese choroby MeSH
- Hodgkinova nemoc farmakoterapie genetika imunologie patologie MeSH
- kohortové studie MeSH
- lidé MeSH
- lidské chromozomy, pár 9 MeSH
- MHC antigeny II. třídy biosyntéza genetika imunologie MeSH
- nivolumab terapeutické užití MeSH
- prediktivní hodnota testů MeSH
- prezentace antigenu MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze II MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
