Prognosis of patients with Hodgkin lymphoma and indeterminate response to PD-1 inhibitor therapy: considerations for application of LYRIC criteria in real clinical practice

doi:10.21203/rs.3.rs-4874864/v1

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Prognosis of patients with Hodgkin lymphoma and indeterminate response to PD-1 inhibitor therapy: considerations for application of LYRIC criteria in real clinical practice

https://doi.org/10.21203/rs.3.rs-4874864/v1

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PD-1 inhibitors have shown unconventional response patterns in classic Hodgkin lymphoma (cHL). These include the phenomenon of pseudoprogression, highlighting the need for specialized response criteria such as the LyRIC, which stringened definitions for disease progression with introduction of indeterminate response category. Despite their potential utility, these provisional criteria are currently underutilized and require further refinement through clinical practice data collection.

In this retrospective study LyRIC criteria were systematically used for response assessments in 180 patients with refractory cHL treated with nivolumab. Median follow-up was 60 months. Indeterminate response (IR) was a frequent phenomenon in study population: at 3 months of therapy 63 (35%) patients had an indeterminate response (IR1 7%, IR2 23%, IR3 6%). Among them 18 (29%) achieved an objective response with continued monotherapy. There were no differences in OS or TTNT depending on the type of IR. IR was the best achieved response in 45 (25%) patients. Patients with IR had favorable prognosis with no difference in OS, PFS and TTNT comparing to patients with PR when subsequent therapy was initiated due to disease progression.

Patients with IR may achieve prolonged disease control or a deeper response upon continuing treatment. These findings support the broader implementation and adjustment of LyRIC criteria in clinical practice to enhance decision-making in cHL patients treated with immunotherapy.

Hodgkin lymphoma

relapsed and refractory disease

PD-1 inhibitors

nivolumab

indeterminate response

LYRIC criteria

immunotherapy

The treatment landscape for patients with relapsed and refractory classic Hodgkin lymphoma (r/r cHL) has changed significantly with the introduction of new targeted agents and immunotherapy. The anti-CD30 antibody-drug conjugate, brentuximab vedotin (BV), received approval in 2011, marking a significant milestone by improving the overall and progression-free survival (OS and PFS) of r/r cHL after autologous stem cells transplantation (auto-HSCT) [1, 2]. Subsequently, the approval of two programmed death-1 (PD-1) inhibitors, nivolumab (Nivo) and pembrolizumab, in 2016 and 2017, respectively, further revolutionized treatment results, with overall response rates ranging from 69–75%. More importantly, the risk of death decreased dramatically and median OS was not reached after 5 years of follow-up. [3, 4]. These advances have opened the door for PD-1 inhibitors as a key component of second- and first-line therapy for cHL. [5, 6].

Pseudoprogression is a controversial clinical and radiological phenomenon characterized by an increase in tumor size, metabolic activity, or the appearance of new lesions during immunotherapy [7]. This condition does not necessarily associate with a dismal prognosis or imminent patient mortality but can instead be transient, displaying considerable variability across sequential radiological evaluations [8]. The understanding of biological mechanisms of pseudoprogression varies, as heterogeneous dynamics during immunotherapy do not necessarily imply absence of tumor activity [9].

The clinical importance of this phenomenon lies in the promising prognosis observed in cHL patients even in the absence of an objective response or with heterogeneous dynamics during therapy with checkpoint inhibitors (CPI). Notably in cases of "treatment beyond progression" [10], delayed therapeutic responses were noted in patients who received continued immunotherapy post-radiological progression.

Emerging discrepancies in the interpretation of the CPI effectiveness have led to changes in standard response criteria for solid tumors. The iRECIST (Response Evaluation Criteria In Solid Tumor) immunological response criteria were proposed and included in subsequent clinical trials of CPI therapy in patients with solid tumors [11]. It was concluded that the use of standard response criteria would have resulted in underestimation of response in 15% of patients, potentially leading to premature discontinuation of effective therapy [12].

A similar situation arose in the treatment of patients with lymphoma with PD-1 inhibitors. By analogy with solid tumors, LyRIC (The lymphoma response to immunomodulatory therapy criteria) criteria were developed specifically for lymphoma patients to optimize CPI therapy strategy. The main difference between LyRIC and Lugano criteria is the introduction of more stringent criteria for disease progression, as well as the introduction of the indeterminate response (IR) category. Three types of IR are described in a report of Cheson et al [13].

However, only a few studies have applied the LyRIC criteria and analyzed the incidence of IR [11, 14–18]. The pooled incidence of pseudoprogression varies from 10 to 19% according to a previously published meta-analysis authored by Lee AJ et al. [19], but can reach 29% according to some studies [18]. This indicates an underestimation of this issue by the professional community.

This report focuses on evaluating the incidence and prognosis of IR among patients with r/r cHL undergoing immunotherapy, aiming to contribute to the development of an optimal treatment strategy informed by the most current understanding of response evaluation criteria.

This retrospective study included 180 patients with cHL who were treated with Nivo 3 mg/kg or 40 mg. The inclusion of the 40 mg dosage regimen was based by an ongoing Nivo40 clinical trial aimed at assessing its safety and efficacy (NCT03343665) [20]. This trial notably incorporated the prospective use of the LyRIC criteria to evaluate treatment outcomes. Given findings from the Nivo40 trial, which suggested that the treatment outcomes for patients receiving the 40 mg dose were comparable to those observed under the standard dosing regimen, we elected to analyze the data from the entire patient population collectively. Inclusion criteria were age over 18 years, a histologically confirmed diagnosis of cHL, relapsed or refractory disease. This study was performed in accordance with the Declaration of Helsinki and approved by the institutional review board. All enrolled patients gave written informed consent. The response was assessed by positron-emission tomography/computed tomography (PET/CT) using LyRIC and Lugano criteria every 3 months. All patients that received at least one cycle of therapy were included in the efficacy analysis.

The overall response rate (ORR), OS, PFS, time to next treatment (TTNT) were analyzed. Overall response rate was defined as the proportion of patients with complete response (CR) or partial response (PR) in measurable lesions. Progression-free survival was defined as the time from the first Nivo cycle initiation to disease progression, relapse, or death and censored by the time of additional therapy initiation; OS was defined as the time from the first Nivo cycle initiation to death from any cause; TTNT was defined as time from the first dose of CPI to initiation of a subsequent treatment. In each survival outcome, data was censored at the date of the last contact for patients who have not experienced the events of interest during their follow-up.

As part of the study, an analysis of the survival of patients who achieved an IR at the time of the first restaging (3 months) was conducted. Additionally, to analyze the hypothesis that the prognosis of patients whose best response was IR is comparable to those who achieved a PR, a comparison of survival in these groups was conducted. Due to instances where therapy was changed without disease progression being established, but due to the registration of an indeterminate response, the most optimal survival endpoints for patient analysis were overall survival and time to next therapy, whereas progression-free survival could only serve as an additional endpoint.

In order to assess potential factors affecting the probability of IR achievement at the time point of 3 months Nivo therapy and the probability of further overall response achievement at any time point after 3 months univariable and multivariable linear regression was applied. With these regards, the following factors at the time of nivolumab therapy initiation were evaluated: age, sex, disease stage, B symptoms, bulky disease, autologous stem cell transplantation, brentuximab vedotin, number of previous therapy lines and nivolumab dose.

Morphological and immunohistochemical methods in primary biopsies were performed as previously described. [21] The expression of the following markers in the tumor microenvironment was analyzed: CD68, CD163, PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD163/c-maf.

The descriptive statistics methods were applied when appropriate. Chi-square test was used for categorical variables, and ‘Mann-Whitney’ test - for continuous variables. The survival probability was estimated using the Kaplan–Meier method with 95% confidence intervals (CIs) estimates. Data analysis was performed using R version 2023.09.1 + 494 (2023.09.1 + 494) software.

Patient’s characteristics

One hundred eighty patients with r/r cHL included in this study were treated with Nivo monotherapy between February 2016 and July 2023 in RM Gorbacheva Research Institute, Pavlov University. Demographics and baseline disease characteristics for all included patients are presented in Table 1.

The median age at Nivo initiation was 31 (range 18–67) years, 114 (63%) patients had primary refractory disease, and 25 (14%) had relapsed within 1 year of frontline therapy. The majority of patients received BEACOPP (n = 90, 50%) or ABVD (n = 67, 37%) regimens as first-line treatment for cHL. Before starting Nivo therapy, 62 (34%) patients had undergone auto-HSCT and 85 (47%) patients had BV treatment. The dose of Nivo was 3 mg/kg in 114 (63%) patients and 40 mg in 66 (37%) patients.

Table 1

Patient’s characteristics at nivolumab initiation
Characteristics	n = 180
Age, median (range)	31 (18–67)
Sex, n (%) Male Female	85 (47) 95 (53)
Disease stage, n (%) 3–4	153 (85)
Prior lines of therapy, median (range)	4 (1–10)
Prior radiotherapy, n (%)	111 (62)
Prior auto-HSCT, n (%)	62 (34)
Prior BV, n (%)	85 (47)
Progressive disease, n (%)	146 (81)
B symptoms, n (%)	99 (55)
Bulky (> 10cm), n (%)	16 (9)
Extranodal disease, n (%)	121 (67)
Dose of Nivo, n (%) 3 mg/kg 40 mg	114 (63) 66 (37)
Number of Nivo cycles, median (range)	21 (1–49)

Nivolumab efficacy in the entire cohort

All patients were included in the efficacy analysis. Median follow-up was 60 (range, 9–99) months. The overall response rate was 68%. According to LyRIC criteria a CR as the best response with median of 6 (1–42) cycles was achieved by 67 (37%) patients, PR by 56 (31%), stable disease (SD) by 11 (6%), progressive disease (PD) by 1 (1%) patient. An indeterminate response (IR) as the best response was established in 45 (25%) patients. Based on the LyRIC criteria definitions, the frequency of CR, PR, and SD corresponds to the Lugano criteria [Figure 1A].

At the data cut-off, the median OS was not reached, 5-year OS was 93.7% (95% CI: 90.0-97.6). Median PFS was 20.9 months (95% CI: 18.8–24.8 mo) with 5-year PFS of 23.0% (95% CI: 16.0-33.1) [Figure 1B].

One hundred forty five (81%) patients required additional therapy due to the progression of disease (n = 104, 58%), insufficient response (n = 34, 19%), or as the consolidation (n = 7, 4%). Nivolumab-contained regimens were used in 127 (88%) patients, allogeneic stem cell transplantation (allo-HSCT) was performed in 34 (23%) patients. It is important to note that among 34 patients who initiated therapy due to insufficient response, none met disease progression criteria. The decision to switch therapy as well as decisions regarding transplantation were made at the discretion of the treating physician, often involving collaborative discussions between the doctor and the patient.

Prognosis of patients who achieved indeterminate response at the moment of the first assessment of response (3 months)

At the moment of first assessment of response (3 months), 63 (35%) patients had an IR. Among them, after 3 more months of Nivo therapy, 9 (14%) patients achieved a CR or PR, 30 (48%) patients maintained an IR, 18 (29%) patients transformed to a PD, while the therapy was discontinued in 4 (6%) patients. After 12 months of Nivo therapy, 8 (13%) more patients achieved an objective response, including those for whom therapy was continued after initial LyRIC PD (n = 4, 6%); 15 (24%) patients saved an IR and 6 (10%) patients developed a PD in this group. The diagram with the evolution of an IR is demonstrated in Fig. 2. In total, with continued Nivo monotherapy after an IR at 3 months, 18 (29%) patients achieved a CR or PR as the best response at different stages of therapy.

Median OS in patients with IR at the 1st assessment of response was not reached, 5-year OS was 89,7% (95% CI: 82.1–97.9). Median PFS was 17,9 (95% CI: 11.5–25.9) months with 5-year PFS of 8,3% (95% CI: 1.7–41.6) Median TTNT 11,7 (95% CI: 9.8–14.1) months, 5-year TTNT 3% (95% CI: 5.5–19.0). [Figure S1].

Type of indeterminate response at the moment of the first assessment of response (3 months)

Type 1 IR (IR1), type 2 (IR2) and type 3 (IR3) were documented in 12 (7%), 41 (23%) and 10 (6%) patients, respectively.

OS and TTNT were analyzed depending on the type of IR at first restaging. While TTNT\OS in the IR1 group was numerically lower, there was no statistically significant difference between groups: median OS was not reached, 5-year OS 75% (95% CI: 54.1–100) vs 94.5% (95% CI: 87.3–100) vs 90% (95% CI: 73.2–100) respectively, p = 0.28 [Figure 3А]; median TTNT 11,2 (95% CI: 7.5-NA) vs 12,9 (95% CI: 9.7–15.2) vs 17,9 (95% CI: 7.7-NA) months, 5-year TTNT 8,3% (95% CI: 1.3–54.4) vs 5,0% (95% CI: 1.3–19.3) vs 0%, respectively, p = 0.45. [Figure 3B].

Different types of IR were also compared with CR and PR (PD and SD were excluded from the analysis due to the limited number of cases). A significant difference was observed in the OS duration when comparing IR1 with CR and PR, as well as in the duration of TTNT for patients with IR1 and IR2 versus CR [Table S1].

Prognostic factors for indeterminate response at the first assessment of response and evolution of indeterminate response to objective response

An association between different clinical factors (age, sex, disease stage, B symptoms, bulky disease, prior autologous stem cell transplantation, previous therapy with brentuximab vedotin, general number of prior therapy lines, nivolumab dose) and IR achievement in 3 months of Nivo therapy was analyzed. There were no significant associations among analyzed factors [Table S2].

There were also no significant associations between analyzed clinical factors and evolution of IR (at 3 months of the therapy) to objective response (CR/PR) [Table S3].

During the analysis of the potential impact of various immunohistochemical factors on the evolution of an IR into an objective response (CR/PR), only the increased expression of LAG3 was found to be significant negative prognostic factor (OR 0.77 (95% CI, 0.57–1.04), p = 0.0016) [Figure S2].

Indeterminate response as the best response to nivolumab therapy

Indeterminate response as the best response to treatment was achieved by 45 (25%) patients. Comparing these patients with those who achieved PR (n = 56, 31%) as the best response to Nivo therapy, no statistically significant differences were obtained for OS and PFS: 5-year OS 92.5% (95% CI: 84.7–100) vs 90.0% (95% CI:82.1–98.8), p = 0.87; median PFS 11,5 (95% CI: 8.5-NA) vs 14,3 months (95% CI: 12.4–21.9), 5-year PFS 0% vs 4,7% (95% CI:0.7–30.5) respectively, p = 0.49 [Figure 4A,B].

At the same time the median TTNT was 10,3 (95% CI:8.7–11.8) vs 12,7 (95% CI:12.2–15.2) months and 5-year TTNT 0% vs 1,9% (95% CI: 0.2–13.5), respectively, p = 0.035 [Figure 4C]. Because the presence of active lesions in the IR group may have led to early initiation of additional therapy before the progression occurred, we performed a subgroup analysis of TTNT for patients in whom additional therapy was initiated due to disease progression. There was no difference in TTNT for the PR and IR groups when therapy was changed due to PD: median TTNT was 10,9 (95% CI:9.1–13.4) vs 13,7 (95% CI:12.2–16.3) months and 5-year TTNT was 0% vs 2,7% (95% CI:3.9–18.8), respectively (p = 0.1) [Figure 4D].

This study demonstrates a high frequency of the indeterminate response or "pseudoprogression" in cHL patients treated with PD-1 inhibitors, which is in good agreement with a previously published experience [19]. Thus, in this population the response can be incorrectly interpreted, and possibly effective therapy may be discontinued. Therapy after disease progression is an extremely vague recommendation, which in some cases does not allow for a correct decision, especially in the context of limited experience of using PD-1 inhibitors. Therefore, it seems important to apply LyRIC criteria to formalize the concept of "pseudoprogression" and the possibility of building relevant treatment algorithms. The integration of LyRIC criteria, which include the IR, is pivotal in advancing decision-making and reimbursement policies that currently rely heavily on radiologic responses [13]. By distinguishing IR from the traditional metrics of progressive disease, LyRIC criteria mitigate the issue of progression overestimation. This distinction is crucial for ensuring that reimbursement policies align with a more nuanced understanding of patient responses, facilitating the continuation of effective treatments and optimizing healthcare resource use.

An important task for developing approaches to the use of PD-1 inhibitors is the analysis of the prognosis of patients who develop an IR at the time of the first restaging in terms of the subsequent evolution of IR. In our study, we found that 10% of patients in the entire group achieved a CR or PR after a transient period of IR. In general, the prognosis of patients with initial IR is very encouraging, with 89,7% 5-year OS in our study. Clinical prognostic factors did not associate with probability of IR achievement or with evolution of IR to CR or PR.

In our analysis, we specifically focused on patients who initially presented with an IR and for whom primary biopsy material was available. Interestingly, we observed a significant association between the level of LAG-3 and the subsequent treatment outcomes: a lower level of LAG-3 was linked to the achievement of a CR or PR following an initial IR. Thus, the tumor microenvironment of cHL is an important area of research which holds promise to deepen our understanding of biological mechanisms underlying IR and could help determine new prognostic factors for patients treated with immunotherapy. The prognostic significance of LAG-3 has previously been demonstrated in patients with HL during standard chemotherapy [22]. We also see a significant number of patients maintaining an IR for a prolonged period of time, which may also be a green light for the possibility of continuing therapy for a long period with a good quality of life for patients, in the absence of severe adverse events. We also did not see a difference in patient survival depending on the IR type.

Evaluating the prognosis for patients who maintain an IR without transitioning to another response type or developing PD over a prolonged period presents a significant challenge. According to the LyRIC criteria, upon the development of PD, the date of this event should be retrospectively attributed to the first IR [13]. However, the adequacy of this requirement is questionable in cases when this progression occurs after a significant interval of continuous treatment during which the patient exhibits no clinical signs of progression and maintains a good quality of life. To address this, we decided to analyze the value of the IR as the best response in comparison to other response types. Our hypothesis was that the prolonged continuation of disease course with an IR could be similar to SD or PR, thereby aligning it with traditional response categories. Our findings indicate no significant difference between OS and PFS in these groups. Thus, it appears that there is a rationale for interpreting an IR as an independent category that should not be retrospectively reevaluated as PD.

Limitations of this study include a retrospective design within a single institution, which may lead to the selection bias, limited number of patients and the significant proportion of patients who received additional treatment after Nivo therapy. Furthermore, it is important to note that within the scope of this study, the additional therapy for patients who exhibited the IR was not systematic.

It is worth noting the numerically higher OS in our group of patients (5-year OS 93.7%) compared to pivotal clinical study (5-year OS 71.4%) [4]. This can be explained by the use of additional therapy options including combinations of Nivo with chemotherapy and targeted therapy, as well as allo-HSCT [15, 16, 23].

Our data stress the need to reconsider the LyRIC criteria in terms of the status of IR and to highlight it as a separate response variant for forming a presentation of the tactics for managing such patients.

Diminishing prognostic utility of PET-CT in immunotherapy recalls the incorporation of novel diagnostic modalities, such as circulating tumor DNA and other soluble factors, to more accurately assess the depth and durability of response [24, 25]. This shift underscores a broader transition in oncological practice towards more personalized, biomarker-driven strategies that reflect the complex interplay between tumor biology and therapeutic intervention. By embracing a more nuanced understanding of IR and integrating innovative diagnostic tools, we can refine our approach to immunotherapy, ultimately enhancing patient outcomes and quality of life.

Our study emphasizes the need to integrate the LyRIC criteria into clinical practice for a more accurate assessment of PD-1 inhibitor therapy responses in cHL. Recognizing the IR highlights the importance of adjusting treatment strategies to avoid premature discontinuation of effective therapies. Our findings set rationale for a re-evaluation of current response criteria to better align with real-world outcomes and support the incorporation of novel diagnostic tools for a deeper understanding of patient prognosis.

Conflict of interest

The authors declare that they have no conflict of interest. Also, there is no financial relationship with any organization for this project.

Ethical approval

This study was performed in accordance with the 1964 Helsinki declaration and approved by the institutional review board. All enrolled patients gave written informed consent.

Funding

This research was funded by the Russian Science Foundation research grant (project number 22-75-00117).

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Acknowledgements

The authors would like to thank Professor Philippe Armand for his comments and for assistance in the preparation of the manuscript.

Authors' contributions

Conception and design: Fedorova LV, Lepik KV, Mikhailova NB, Kulagin AD, Moiseev IS

Provision of study materials or patients: Fedorova LV, Lepik KV, Mikhailova NB, A. Gusak

Collection and assembly of data: Fedorova LV, Lepik KV, Mikhailova NB, A. Gusak

Data analysis and interpretation: Fedorova LV, Lepik KV, Mikhailova NB, Kotselyabina PV, Moiseev IS

Manuscript writing: Fedorova LV, Lepik KV, Kotselyabina PV, A. Gusak, Baykov VV, Mikhailova NB, Kulagin AD

Final approval of manuscript: All authors

Accountable for all aspects of the work: Fedorova LV, Lepik KV

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Prognosis of patients with Hodgkin lymphoma and indeterminate response to PD-1 inhibitor therapy: considerations for application of LYRIC criteria in real clinical practice

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Abstract

Figures

Introduction

Materials and methods

Results

Patient’s characteristics

Nivolumab efficacy in the entire cohort

Type of indeterminate response at the moment of the first assessment of response (3 months)

Indeterminate response as the best response to nivolumab therapy

Discussion

Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1