Introduction The checkpoint inhibitors (CI) nivolumab and pembrolizumab which target PD1 are established treatments for relapsed/refractory classic Hodgkin Lymphoma (cHL). The Keynote-087 and -204 trials included patients who were unsuitable for autologous stem cell transplant (ASCT). Published data suggests that patients who receive CI prior to ASCT have better outcomes (Spinner et al, Blood 2023 & Desai et al AJH 2022). The effect of CI prior to ASCT was investigated in a retrospective single centre analysis.

Methods The local transplant database was used to identify adult and paediatric patients who had an ASCT for relapsed/refractory cHL 2017-2024. Demographic, treatment, stem cell collection and response data was collected. Analysis was performed using Graphpad Prism version 10.

Results 94 patients were identified with median age 27 (IQR 20-39, range 12-72) and equal numbers of female and male patients. First line treatment was ABVD or AAVD (64) or OEPA (22) in most patients. 41 patients were primary refractory. Initial salvage was with GEMP/GDP in 58 patients. 44 received brentuximab vedotin (BV). 50 patients had ASCT consolidation after 1st line salvage and 44 had 2 or more lines of salvage prior to ASCT. Prior to ASCT 17 (18%) patients were not in CR. 16(17%) patients had received radiotherapy at some point in their treatment.

The CI group included 23 patients at any line of salvage (nivolumab 4; pembrolizumab 19). CI was given as 1st/2nd/3rd line salvage in 5/11/7 patients respectively. 20 patients had a CI as their last line of therapy prior to ASCT. 4 patients had a CI in combination with BV.

The median number of CI doses was 4.5 (IQR 3.25-7.75) with the last dose given a median of 42 days pre ASCT (IQR 31-76).

All patients were conditioned with LEAM (lomustine, etoposide, cytarabine, melphalan). Post ASCT, 3 patients had consolidative radiotherapy and 6 received BV maintenance (4 in no-CI group, 2 in CI group).

CI treatment pre-ASCT resulted in improved progression free survival (PFS) (p=0.047) with 0 relapses in the CI group at analysis and 2 year PFS of 79.1% (CI 69.1-90.6) in the no-CI group.

In multivariate analysis female sex was associated with improved PFS (HR 0.28 [CI 0.086-0.79], p=0.021) and failure to be in CR pre ASCT was associated with reduced PFS (HR 4.3 [1.15-13.5] p=0.017). There was a trend towards worse outcomes in primary refractory patients (HR 2.64 [0.95-7.53] p=0.061). Age, prior BV treatment and number of lines of therapy pre ASCT were not associated with PFS. A HR was not calculable for CI therapy as there were 0 events. Overall survival was 87.7% (95% CI 75-100) at 5 yrs for the whole cohort with 5 deaths.

The CI group had fewer patients in CR prior to ASCT (65% vs 87%, p=0.017) and fewer patients who had received only 1 line of salvage prior to ASCT (8.6% vs 68%, p<0.01). There was shorter median follow up in the CI group (18 vs 29 months).

15 patients relapsed post ASCT. 13 patients received CI for relapse and 9 had allogeneic stem cell transplants.

Immune complications affected 5 patients (2 myocarditis, 1 colitis, diabetes and pneumonitis).

14 patients were on a CI at time of stem cell harvest with median time between last CI dose and collection of 27.5 days. The mean CD34+ stem cells harvested was lower in CI treated patients 3.41 vs 4.23 (106/kg, p=0.025). CI was given a median of 30 days pre-harvest (IQR 20.8-35.5). CD34 doses infused were not associated with PFS.

Conclusions Previous CI treatment is associated with improved PFS post ASCT in our centre despite lower pre-ASCT CR rates and more lines of salvage therapy.

Failure to be in CR pre ASCT was associated with shorter PFS but despite the CI group having fewer patients in CR, they had superior PFS. There is a trend toward reduced PFS in patients who were initially primary refractory.

It is unclear if R/R patients treated with CI benefit from routine ASCT. Spinner et al, Blood 2023 found a PFS of 91% at 4 years in CI treated patients post ASCT. Our data supports this and suggests pre-ASCT response is less important in CI treated patients. Most of the no-CI group were salvaged with subsequent CI for relapse post ASCT with or without subsequent allogeneic transplant.

CI treatment prior to ASCT may alter cHL disease biology leading to increased sensitization to subsequent high dose cytotoxic chemotherapy although more exploratory data assessing the mechanism is needed.

We are planning a multi-centre analysis to investigate further.

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2025
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