The lym Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the lym Hub cannot guarantee the accuracy of translated content. The lym and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.
The Lymphoma & CLL Hub is an independent medical education platform, sponsored by Beigene, Johnson & Johnson and Roche, and supported through educational grants from Bristol Myers Squibb, Incyte, Lilly, and Pfizer. View funders.
Now you can support HCPs in making informed decisions for their patients
Your contribution helps us continuously deliver expertly curated content to HCPs worldwide. You will also have the opportunity to make a content suggestion for consideration and receive updates on the impact contributions are making to our content.
Find out moreCreate an account and access these new features:
Bookmark content to read later
Select your specific areas of interest
View lym content recommended for you
Classical Hodgkin lymphoma (HL) is a highly curable disease, however, up to 30% of patients with advanced disease relapse. In these patients, salvage chemotherapy and autologous stem cell transplant (ASCT) can induce long-term remissions. However, those patients relapsing after ASCT have poor outcomes with overall survival (OS) ranging from 10.5–27.6 months.1
HL is uniquely vulnerable to PD-1 blockade and as such, anti-PD1 antibodies such pembrolizumab and nivolumab are being investigated in HL. In recent studies, checkpoint blockade with anti-PD1 antibodies has proved efficacious in relapsed/refractory (R/R) HL, with overall response rates (ORRs) of approximately 70% and complete responses (CRs) of up to 20%. In 2016 and 2017, the United States (US) Food & Drug Administration (FDA) approved nivolumab and pembrolizumab, respectively, in this setting.1
However, questions remain on the long-term efficacy and optimal management of R/R HL, including duration of treatment and consolidation strategies following salvage chemotherapy and ASCT. The efficacy of pembrolizumab as consolidation post-ASCT was recently investigated by Philippe Armand, Dana-Farber Cancer Institute, Boston, US, and colleagues, in an article published in Blood.2 Another study investigating consolidation strategies was published in the European Journal of Cancer by, Guillaume Manson, University Hospital of Rennes, Rennes, FR, and colleagues, who investigated the use of nivolumab, with and without allo-HSCT.1
The study by Armand et al., was a phase II (NCT02362997), multicohort, open-label study in the US investigating pembrolizumab as consolidation post-ASCT. The authors’ hypothesis was that pembrolizumab would improve progression-free survival (PFS) at 18 months post-ASCT from 60% to 80%. Additionally, the treatment would be considered promising if 22 of the 30 patients treated were alive and progression-free at 18 months.
Type of AE
N (%)
≥1 Grade ≥2 AE
24 (80%)
≥1 Grade ≥3 AE
9 (30%)
Treatment-related AE (TRAE)
≥1 Grade ≥2 TRAE
15 (50%)
≥1 Grade ≥3 TRAE
8 (27%)
In total, 39 immune related AEs (irAEs) occurred in 13 patients (43%). The most frequent grade ≥ 2 events were pneumonitis, cough or dyspnea.
The study by Manson et al., retrospectively analyzed 78 adult patients with R/R HL who were treated with nivolumab in the French Early Access Program (EAP) and compared their outcomes based on consolidation with or without allo-HSCT.1
The French EAP included patients who had received three lines of chemotherapy including brentuximab vedotin and ASCT, or four lines of chemotherapy if the patient was ineligible for transplant.1
The efficacy results for the whole cohort (n= 76) are shown in Table 2. The PFS rate was higher in patients achieving a CR with nivolumab compared to those achieving a PR, but no difference was seen in OS.
Table 2. Outcomes of whole cohort (n= 76)Endpoint
Whole cohort
Confidence interval, range, p value
Best ORR
65.8%
90% CI, 55.82–74.80
CR
38.2%
-
PR
27.6%
-
Median time to response
2.6 months
95% CI, 2–4
Median time to best response
2.7 months
Median duration of response
24.3 months
95% CI, 9.9–not evaluable (NE)
Median PFS
12.1 months
95% CI, 7.3–26.2
3-year PFS
32%
-
PFS of patients in CR vs PR with nivolumab
Not reached vs 9.3 months
p< 0.001
Median OS
38.7 months
95% CI, 38.7–NE
3-year OS
65%
-
Table 3. Rates of relapse/progression by response to nivolumabResponse to nivolumab
Relapse or progression, N (%)
CR or PR (n= 50)
23 (46%)
CR (n= 29)
7 (24%)
PR (n= 21)
16 (76%)
In total, 17 patients received allo-HSCT after nivolumab, 13 of whom had achieved an objective response (CR or PR) to nivolumab therapy. The four other patients transplanted had PD (n= 1) or had received salvage therapy (n= 3). Of the patients not in CR at transplant, five of six converted to CR post-allo-HSCT. At a median follow-up of 29.2 months, 13 patients of the 17 transplanted remained alive and disease-free. PFS and OS rates at one-year post-transplant were 76% and 82% respectively.
To evaluate if there was a benefit of consolidation with allo-HSCT, responses were compared between patients who responded to therapy and received transplant (n= 13) to those who responded but did not receive allo-HSCT (n= 37). At baseline, transplanted patients were younger and had a shorter duration of treatment with nivolumab, but there were no differences in relation to number of prior lines of therapy or disease stage. The time to best response was shorter in the transplanted group (2.4 months) compared to the non-transplanted group (1.8 months).
Table 4 shows the AEs reported during the study. In total, 54 patients were alive at time of analysis. The main cause of death was lymphoma progression (n= 14, 58.3%)
Table 4. AEs reported during the studyAEs
N (%)
Total AEs
107
Number of patients experiencing an AE
40 (51.3%)
Grade ≥3 AEs
62
Number of patients experiencing a grade ≥3 AE
29 (37%)
Serious AEs (SAEs)
28
Number of patients experiencing a SAE
16 (20.5%)
Graft-versus-host disease (GvHD)
Treatment-related mortality (TRM)
The study by Manson et al., has shown that in patients with R/R HL treated with nivolumab, most eventually progress despite high initial ORRs, especially those who do not achieve a CR. Patients who underwent allo-HSCT after nivolumab therapy however had a longer PFS compared to those who did not and had a lower relapse rate. At 34.3 months follow-up, this did not translate to a benefit in OS.1 The results of this study show a benefit of allo-HSCT as consolidation following anti-PD1 therapy, however the results are interpreted cautiously due to the retrospective nature of the study and a limited patient sample. As there was no benefit in OS, it is essential to analyze the risk/benefit ratio and consider the possibility of re-sensitization with salvage chemotherapy as an alternative treatment option in this population. Prospective studies are required to identify the patients who benefit most from consolidation allo-HSCT after anti-PD1 therapy.
Meanwhile, the study by Armand et al., showed high PFS rates and cure rates can be achieved with pembrolizumab as post-ASCT consolidation in patients who do not respond to frontline therapy. The results also support the initiation of a further randomized trial of pembrolizumab as post-ASCT consolidation. Another study (NCT03057795) is investigating the combination of brentuximab vedotin with nivolumab as consolidation therapy for patients with R/R HL.
References