Checkpoint-primed allo-HCT in HL: cure gains, risk remains Free

In this issue of Blood, Perales et al¹ assess effects of checkpoint inhibition (CPI) before allogeneic stem-cell transplantation (alloSCT) for relapsed/refractory (R/R) classic Hodgkin lymphoma (HL) in a joint Center for International Blood and Marrow Transplant Research/European Society for Blood and Marrow Transplantation analysis of 2186 adult patients.

The approved CP inhibitors, nivolumab and pembrolizumab, show high objective response rates in R/R HL, but complete response rates are modest. Longer follow-up of pivotal trials indicates that most patients eventually relapse, with a median progression-free survival (PFS) of ∼14 months and 5-year PFS of <20%.^2,3 After failure of CPI, these patients experience poor outcomes.⁴ Due to its curative potential, alloSCT is frequently used to consolidate remissions achieved in heavily pretreated patients with R/R HL. Given the potential of immune-related adverse events and aggravation of graft-versus-host disease (GVHD) with CPI therapy, there have, however, been concerns and uncertainty regarding the use of alloSCT to either consolidate remissions achieved with or failure of CPI. Perales et al address these uncertainties by comprehensively evaluating key outcomes such as PFS, overall survival (OS), relapse rates, nonrelapse mortality (NRM), and GVHD in the largest series of patients reported to date, with R/R HL, undergoing alloSCT.

Of the 2186 patients receiving alloSCT between 2008 to 2023, prior exposure to CPI therapy was reported in 600 patients (27%). Interestingly, the proportion of patients without prior autologous stem-cell transplantation (autoSCT) was higher among those with CPI exposure (38% vs 26%), as was the use of posttransplantation cyclophosphamide (PTCy) as GVHD prophylaxis (56% vs 35%). As expected, lower rates of refractory disease at the time of alloSCT were reported with prior CPI exposure (15% vs 21%). The median time between CPI exposure and alloSCT was 10 months with a broad range of 1 to 217 months.

Patients with prior CPI exposure had longer 1-year PFS (69% vs 58%; hazard ratio, 0.81; 95% confidence interval, 0.67-0.98) and lower relapse rates (13% vs 29%; hazard ratio, 0.58; 95% confidence interval, 0.45-0.76), whereas no significant differences were observed in 1-year OS (76% vs 79%) or NRM (18% vs 13%). In line with previous reports, the incidence of acute GVHD (grades 2-4: 40% vs 27%; grades 3-5: 16% vs 9%) was higher after prior CPI exposure. Taken together, these findings hint at increased disease control with alloSCT after prior CPI exposure, potentially due to an augmented graft-versus-lymphoma effect, at the cost of higher GVHD (see figure). No differences in chronic GVHD were observed (31% vs 34%).

These observations were confirmed in multivariate analysis and propensity score–matched approaches, which also revealed additional insights of potential clinical relevance; reduced rates of acute and chronic GVHD were observed with PTCy, which also resulted in improved OS in the setting of prior CPI exposure. Similar to the autoSCT setting,⁵ impaired performance status and the failure to achieve a remission before transplant were associated with significantly inferior PFS and OS as well as increased NRM. Lastly, increased age was associated with worse prognosis, whereas female sex and more recent alloSCT resulted in improved outcomes.

Further informing clinical practice, the authors evaluated the impact of time between last CPI dose and alloSCT, because it is often recommended to perform alloSCT only after a certain wash-out period, for example, >3 months. Importantly, the authors could not identify any difference regarding PFS, NRM, or OS based on the interval between CPI and alloSCT. Although the registry-based data are not granular enough regarding exact timings and on other intermittent therapies, these observations are important, because aiming for prolonged wash-out periods comes at the risk of interval disease progression and a closed window of opportunity to successfully perform alloSCT.

Notwithstanding these important insights with immediate clinical implications, there are important limitations given the retrospective, registry-based nature of the study. Despite carefully conducted multivariate analyses and propensity score matching, key characteristics known to affect outcomes differ between the CPI exposed and naïve groups. Additionally, the data structure prohibits more detailed analysis regarding the CPI exposure and HL disease course leading up to alloSCT. Hence, it remains unclear whether the benefits in disease control are applicable to patients receiving alloSCT as consolidation for a favorable response to CPI or those failing CPI and receiving additional intermittent treatment(s). To this end, more detailed studies are needed to inform optimal approaches in patients achieving a complete remission (CR) with CPI, where current approaches range from continuing CPI until progression or toxicity, cessation of CPI after CR is maintained for 6 to 12 months or performing a consolidative alloSCT in first CR to avoid dismal outcomes associated with multiply relapsed disease.⁶ 

Of note, the superiority of alloSCT over continuing CPI or watchful waiting in this setting has thus far not been proven, with some data even pointing at the opposite direction.² Moreover, given the excellent outcomes reported for autoSCT after prior CPI exposure with 2-year event-free survival rates of 80% and favorable results even in patients with multiple relapses and [¹⁸F]fluorodeoxyglucose positron emission tomography–positive disease before autoSCT,^7,8 the role of alloSCT in autoSCT naïve patients might be questioned. In fact, as many as 38% of patients in the CPI group in the analysis performed by Perales et al were not exposed to autoSCT before alloSCT. An autoSCT might be the preferred strategy in this setting in the CPI era. In addition, although this is speculative, even a second autoSCT after response to CPI might be an option in patients with multiply relapsed disease. The potential of a second autoSCT has been reported earlier and might be re-evaluated in the CPI era.^7-9 In addition, future research should focus on quality of life and patient reported outcomes which are both usually not available in registries but play a major role in the judgment of therapeutic strategies rich in side effects such as auto- or alloSCT, especially in GVHD due to the latter.

The comprehensive analysis of this large international data set encourages the use of alloSCT with PTCy-based GVHD prophylaxis after CPI exposure to improve outcomes of heavily pretreated patients with R/R HL. Uncertainties remain not only regarding the potentially revised role for autoSCT but also in light of the rapidly changing treatment landscape and increasing use of anti-PD1 CPI in the first-line and relapsed setting.¹⁰ 

Conflict-of-interest disclosure: P.J.B. is an adviser or consultant for Hexal, Merck Sharp & Dohme (MSD), Need Inc, Stemline, and Takeda; holds stock options in Need Inc; has received honoraria from AstraZeneca, BeiGene, Bristol-Myers Squibb/Celgene (BMS), Eli Lilly, MSD, Need Inc, Stemline, and Takeda; reports research funding from BeiGene (institution), BMS (institution), MSD (institution), and Takeda (institution); and reports an Excellence Stipend of the Else-Kröner-Fresenius Foundation. B.v.T. is an adviser or consultant for Allogene, Amgen, BMS/Celgene, Cerus, Gilead Kite, Incyte, Iqvia, Janssen-Cilag, Lilly, MSD, Miltenyi, Novartis, Noscendo, Pentixapharm, Pfizer, Pierre Fabre, Qualworld, Regeneron, Roche, Sobi, and Takeda; has received honoraria from AbbVie, AstraZeneca, BMS/Celgene, Gilead Kite, Incyte, Janssen-Cilag, Lilly, MSD, Novartis, Roche, Serb, and Takeda; reports research funding from Esteve (institution), MSD (institution), Novartis (institution), and Takeda (institution); reports travel support from AbbVie, AstraZeneca, Gilead Kite, Janssen-Cilag, Lilly, MSD, Pierre Fabre, Roche, Takeda, and Novartis; and is member of steering committees for Regeneron (institution) and Takeda.