Do all roads lead to Rome? The heterogeneity of relapsed/refractory diffuse large B-cell lymphoma patients who achieved therapies response and received autologous stem cell transplantation in the era of new targeted drugs

Abstract

In this multicenter study, we aimed to identify the prognostic factors for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) patients who received autologous stem cell transplantation (ASCT) in the era of novel agents and chimeric antigen receptor (CAR) T-cell therapy. A total of 82 relapsed/refractory DLBCL patients receiving ASCT across four transplant centers were enrolled. The 3-year probabilities of disease progression, non-relapse mortality (NRM), progression-free survival (PFS), and overall survival (OS) were 23.5%, 2.8%, 73.7%, and 91.4%, respectively. Patients who received Pola-R-CHP before ASCT had a higher disease progression rate (85.7% vs. 18.4%, P = 0.034) and a poorer PFS (0% vs. 79.9%, P < 0.001) after ASCT compared with those who did not receive Pola-R-CHP. Patients who received BTKi before ASCT had a higher disease progression rate (60.0% vs. 18.2%, P = 0.025) and a poorer PFS rate (23.8% vs. 81.8%, P < 0.001) after ASCT compared with those who did not receive BTKi. In multivariate analysis, receiving novel agents before ASCT was independently associated with a higher risk of disease progression and worse PFS. In summary, we observed the heterogeneity of relapsed/refractory DLBCL patients who achieved therapies response and received ASCT, and some of them might not benefit from ASCT.

Keywords

autologous stem cell transplantation relapsed/refractory DLBCL new targeted drugs diffuse large B-cell lymphoma chimeric antigen receptor T-cell therapy

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin lymphoma (NHL), with an estimated 150,000 new cases annually worldwide¹. R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is the commonly accepted first-line treatment for DLBCL and 60% of patients can achieve long-term survival^1,2. Recently, polatuzumab vedotin-based regimen (e.g. Pola-R-CHP) has further improved the clinical outcomes of DLBCL and the complete response (CR) rate could be up to 82.3% and 91.1% of patients can achieve long-term survival³, which has also been recommended as the frontline treatment.

However, relapsed/refractory DLBCL remains a critical challenge. Autologous stem cell transplantation (ASCT) is a standard care for chemo-sensitive relapsed/refractory DLBCL^4,5. Recently, the rapid development of chimeric antigen receptor (CAR) T-cell therapy may weaken the role of ASCT. The randomized phase 3 trial (ZUMA-7) suggested that CAR-T-cell therapy performed better than conventional intensive chemotherapy plus ASCT in patients who were refractory to first-line treatment or had relapsed within 12 months after the first-line chemoimmunotherapy. However, ZUMA-7 has strict inclusion criteria, for example, patients who received bridging chemotherapy and those with bulky diseases were not included, which is differ from the real-world clinical setting⁶. The BELINDA study, which is much closer to real clinical practice, suggested that CAR-T-cell therapy did not show significant superiority over ASCT⁷. In addition, the median progression-free survival (PFS) for patients with CAR-T-cell therapy is only 3.0 to 8.3 months in real-world studies^6–8. Therefore, even in the era of CAR-T-cell therapy, ASCT still remains an important salvage therapy for relapsed/refractory DLBCL patients.

Previously, several risk factors, such as resistant to chemotherapy before ASCT⁹, time from diagnosis to relapse less than 12 months¹⁰, and higher International Prognostic Index (IPI)⁴ were identified as risk factors for worse clinical outcomes in relapsed/refractory DLBCL patients following ASCT. Nevertheless, these risk factors may evolve since novel agents and cellular therapy become more prevalent. For instance, in patients who have achieved at least partial response (PR) before ASCT, are the clinical outcomes different between patients who received novel agents and those who received conventional chemotherapy? Particularly, are the clinical outcomes comparable between patients who have achieved a therapeutic response after multi-line salvage therapies, including those treated with novel targeted therapy or CAR-T therapy, and those who responded to first-line salvage chemotherapy? Thus far, no studies have addressed these questions. Thus far, no studies have addressed these questions.

Thus, in this multicenter study, we aimed to identify the prognostic factors for relapsed/refractory DLBCL patients who received ASCT in the era of novel agents and CAR-T therapy.

Materials and methods

Patients

This retrospective, multicenter study is designed by Wuhan Tongji Hospital, Beijing Hospital, Shenzhen People’s Hospital, and Peking University Institute of Hematology. Consecutive relapsed/refractory DLBCL patients were screened. The eligibility criteria were as follows: (1) age >16 years at diagnosis; (2) diagnosed with relapsed/refractory DLBCL between 2015 and 2023; (3) patients received salvage therapies and achieved at least stable disease (SD); and (4) received ASCT after salvage therapies as consolidation. The last follow-up was April 1, 2024. The study was approved by the institutional review board of each participating hospital and was conducted in accordance with the Declaration of Helsinki.

Data collection

Investigators accessed clinical databases through the electronic medical record systems of each hospital. Collected data included information of patients’ demographics, histological diagnosis, Ann Arbor stage, lactate dehydrogenase, B symptoms, bone marrow infiltration, IPI, salvage therapies, ASCT, and clinical outcomes. Two experienced lymphoma physicians independently reviewed all data.

Definition

Relapsed/refractory was defined as failure to achieve PR after first-line therapy or disease progression. The criteria of therapeutic response were according to the Lugano classification¹¹. Non-relapse mortality (NRM) was defined as death without disease progression or relapse. PFS event was defined as disease progression or death as a result of any cause. Overall survival (OS) event was defined as death as a result of any causes.

Statistical analysis

Data were censored at the time of death or last available follow-up. The primary outcome was disease progression. The secondary outcomes included NRM, PFS, and OS. The Kaplan–Meier estimator was used to calculate the probabilities of survival, and cumulative incidence function was used to calculate the incidence of engraftment, disease progression, and NRM with competing risk analysis. The univariable and multivariable Cox regression was performed to determine the impact of potential prognostic factors on clinical outcomes. Two-sided P-values were adopted. Independent variables with P > 0.1 were sequentially excluded from the model, and P < 0.05 was considered to be statistically significant. Statistical analysis was performed using the R software 4.2.0 (https://www.r-project.org) and Statistical Package for the Social Sciences 26 (SPSS Inc., IBM, Armonk, NY, USA).

Results

General characteristics of patients

A total of 82 relapsed/refractory DLBCL patients receiving ASCT were enrolled. Prior to ASCT, 22 patients received salvage therapies with novel agents, which included BTKi (n = 15; Supplementary Table 1, Table 1), Pola-R-CHP (n = 7), CAR-T cell therapy (n = 2), and blinatumomab (n = 1), while the remaining 60 patients received traditional chemotherapy (Supplementary Table 2). The baseline characteristics of these two cohorts are compared in Supplementary Table 3. Of the 22 patients treated with novel agents, 15 received them as immediate pre-ASCT salvage therapy. The other seven patients received novel agents in earlier lines of treatment. The median follow-up time was 1014 days (range, 850–1177) days. All patients achieved neutrophil and platelet engraftment. The median time from ASCT to neutrophil and platelet engraftment was 11 days (range, 7–19) days and 13 days (range, 6–52) days, respectively.

Table 1.

Characteristics of refractory/relapsed DLBCL patients receiving ASCT.

Characteristics	n = 82
Age, n (%)
<60 years	59 (72.0)
≥60 years	23 (28.0)
Median age at ASCT, years (range)	50.5 (19–68)
Gender, n (%)
Male	39 (47.6)
Female	43 (52.4)
Number of chemotherapy lines before ASCT, median (range)	2 (1–7)
Courses of chemotherapy before ASCT, median (range)	8 (2–16)
Ann Arbor stage, n (%)
II	17 (20.7)
III–IV	65 (79.3)
International Prognostic Index, n (%)
0–1	18 (22.0)
2–3	48 (58.5)
≥ 4	16 (19.5)
LDH at initial diagnosis, n (%)
Elevated	37 (45.1)
Normal	45 (54.9)
BM involvement at initial diagnosis, n (%)
Yes	59 (71.9)
No	23 (28.1)
Bulky disease at initial diagnosis, n (%)
Yes	75 (91.5)
No	7 (8.5)
Central nervous system involvement, n (%)
Yes	7 (8.5)
No	75 (91.5)
Resistance and progression before ASCT, n (%)
Disease progression ≥ 1 year after CR	16 (19.5)
Primary refractory disease	33 (40.2)
Disease progression <1 year after CR	33 (40.2)
Disease status before ASCT, n (%)
Complete remission	48 (58.5)
Partial remission	31 (37.8)
Stable disease	3 (3.7)
MNC cell counts in graft, median (range, ×10⁶/kg)	9.7 (0.5–28.9)
CD34⁺ cell counts in graft, median (range, ×10⁶/kg)	3.9 (1.14–35.71)

ASCT, autologous stem cell transplantation; BM, bone marrow; LDH, lactate dehydrogenase; MNC, mononuclear cell.

Major transplant outcomes

NRM

Two patients died of infections, and the 3-year cumulative incidence of NRM after ASCT was 2.8% (95% confidence interval (CI): 0%–6.7%).

Disease progression

A total of 17 patients experienced disease progression after ASCT, and the median time from ASCT to disease progression was 150 (range, 69–922) days. The 3-year cumulative incidence of disease progression after ASCT was 23.5% (95% CI: 13.4%–33.7%). In subgroup analysis, the 3-year cumulative incidence of disease progression after ASCT was 85.7% (95% CI: 0%–100%) and 18.4% (95% CI: 9.3%–27.6%), respectively, for patients with and without Pola-R-CHP before ASCT (P = 0.034, Figure 1a). In addition, the 3-year cumulative incidence of disease progression after ASCT was 60.0% (95% CI: 9.1%–100.0%) and 18.2% (95% CI: 8.2%–28.2%), respectively, for patients with and without BTKi therapy after ASCT (P = 0.025, Figure 1b). The 3-year cumulative incidence of disease progression after ASCT was 15.9% (95% CI: 6.2%–25.6%) and 59.2% (95% CI: 21.9%–96.5%), respectively, for patients who received traditional chemotherapies and those who received novel agents (i.e. Pola-R-CHP, BTKi-based therapy, CAR-T cell therapy or blinatumomab; P = 0.016, Figure 1c). The 3-year cumulative incidence of disease progression after ASCT was 0.0%, 34.5% (95% CI: 17.6%–51.5%), and 13.7% (95% CI: 0.9%–26.4%), respectively, for patients with primary refractory disease, with relapsed disease <12 months, and those with relapsed disease ≥12 months (P = 0.010, Figure 1d). Receiving ASCT after ≥ 2 lines of salvage treatments and disease status before ASCT (CR, PR and SD) were not associated with disease progression after ASCT (Supplementary Table 4).

Figure 1.

The 3-year cumulative incidence of disease progression for patients (a) with and without Pola-R-CHP before ASCT, (b) with and without BTKi before ASCT, (c) with traditional chemotherapy and those with novel agents before ASCT, and (d) patients with primary refractory disease, with relapsed disease <12 months, and those with relapsed disease ≥12 months.

In multivariable analysis, receiving novel agents before ASCT was independently associated with a higher risk of disease progression (Supplementary Table 5, Table 2).

Table 2.

Multivariable analysis of clinical outcomes in relapsed/refractory DLBCL patients receiving ASCT.

Outcomes	HR (95% CI)	P-value
Treatment failure as defined by disease progression
Treatment before ASCT
Traditional chemotherapies	1
Novel agents	3.67 (1.37–9.86)	0.010
Treatment failure as defined by progression-free survival
Treatment before ASCT
Traditional chemotherapies	1
Novel agents	4.19 (1.68–10.46)	0.002

ASCT, autologous stem cell transplantation.

PFS

The 3-year probability of PFS after ASCT was 73.7% (95% CI: 63.9%–84.9%). In subgroup analysis, the 3-year probability of PFS after ASCT was 0.0% and 79.9% (95% CI: 70.9%–90.0%), respectively, for patients with and without Pola-R-CHP before ASCT (P < 0.001, Figure 2a). The 3-year probability of PFS after ASCT was 23.8% (95% CI: 52.8%–100.0%) and 81.8% (95% CI: 72.5%–92.3%), respectively, for patients with and without BTKi treatment before ASCT (P < 0.001, Figure 2b). The 3-year probability of PFS after ASCT was 84.1% (95% CI: 75.0%–94.2%) and 29.0% (95% CI: 10.0%–83.6%), respectively, for patients receiving traditional chemotherapies and those receiving novel agents (P < 0.001, Figure 2c). The 3-year probability of PFS after ASCT was 90.9% (95% CI: 75.4%–100.0%), 61.6% (95% CI: 46.6%–81.6%) and 78.1% (95% CI: 63.6%–95.9%), respectively, for patients with primary refractory disease, with relapsed disease <12 months, and those with relapsed disease ≥12 months (P = 0.0495, Figure 2d). Similarly, receiving ASCT after ≥ 2 lines of salvage treatments and disease status before ASCT (CR, PR and SD) were not associated with PFS after ASCT (Supplementary Table 6).

Figure 2.

The 3-year probability of PFS for patients (a) with and without Pola-R-CHP before ASCT, (b) with and without BTKi before ASCT, (c) with traditional chemotherapy and those with novel agents before ASCT, and (d) patients with primary refractory disease, with relapsed disease <12 months, and those with relapsed disease ≥12 months.

In multivariable analysis, receiving novel agents was independently associated with a poorer PFS (Supplementary Table 5, Table 2).

OS

The 3-year probability of OS after ASCT was 91.4% (95% CI: 84.9%–98.3%). In subgroup analysis, the 3-year probability of OS after ASCT was 74.2% (95% CI: 52.4%–100.0%) and 94.8% (95% CI: 89.2%–100.0%), respectively, for patients receiving BTKi and those without BTKi before ASCT (P = 0.021). Other subgroup analysis for OS was shown in Supplementary Table 7. In multivariable analysis, no risk factor was associated with OS after ASCT.

Discussion

In this study, we found that the 3-year probability of disease progression, NRM, PFS and OS were 23.5%, 2.8%, 73.7%, and 91.4% respectively. Additionally, receiving novel agents before ASCT was associated with a higher risk of disease progression and worse PFS. So far, we have identified the subgroups of relapsed/refractory DLBCL patients who could not benefit from ASCT in the era of novel agents and CAR-T therapy.

Autologous stem cell transplantation has been recommended to relapsed/refractory DLBCL patients who have responded to salvage therapies. However, no studies had compared the outcomes between patients who achieved a therapeutic response after 1 line of salvage therapy and those who received two or more lines of salvage therapies. Patients who achieved a therapeutic response after multiple lines of salvage therapies may indicate a lack of sensitivity to chemotherapy, especially for those who were unable to achieve CR after multiple salvage therapies. It is debatable whether these patients should receive ASCT as consolidation. Although receiving ≥ 2 lines of salvage therapies did not impact disease progression and survival after ASCT, more than one third of these patients experience disease progression after ASCT. This suggested that more intensive consolidations, such as allogeneic hematopoietic stem cell transplantation, may be advisable. Recent advances in allogeneic transplantation techniques have led to a reduction in NRM and improved safety^12–16, making this approach a promising avenue for further exploration in the future.

BTKi has emerged as an important salvage therapy for relapsed/refractory DLBCL patients, particularly for those who are resistant to traditional chemotherapies. Wilson et al.¹⁷ reported that an overall response rate (ORR) of 37% for ibrutinib therapy in activated B cell–like relapsed/refractory DLBCL patients, while Yang et al.¹⁸ reported an ORR of 29.3% for zanubrutinib therapy in non-germinal center B-cell like (non-GCB) relapsed/refractory DLBCL patients. In the present study, the majority of patients receiving BTKi had demonstrated resistance to salvage chemotherapies and subsequently exhibited a higher risk of relapse, poorer PFS and poorer OS after ASCT. This suggested that ASCT may not overcome the poor prognosis of chemotherapy resistance even if these patients achieve a therapeutic response following targeted therapies. This phenomenon may be attributed to the fact that ASCT primarily eliminates residual lymphoma cells through conditioning regimens, which essentially consist of intensive chemotherapy. In addition, compared with the traditional chemotherapy group, the novel therapy group had a higher proportion of patients with bulky disease at diagnosis and a higher proportion of patients who did not achieve CR prior to transplantation. This may explain the poorer prognosis observed in the novel therapy group.

Polatuzumab Vedotin was also a novel agent for relapse/refractory DLBCL. Sehn et al.¹⁹ reported that the clinical outcomes of polatuzumab vedotin combined with bendamustine and rituximab (pola-BR) were better than BR in relapsed/refractory DLBCL patients. In the present study, we also observed that patients who achieved therapeutic response after polatuzumab plus chemotherapy showed a poorer OS after ASCT. However, only seven patients received polatuzumab-based therapy as salvage therapy in the present study, and it is premature to make the conclusion that ASCT could not improve the survival of these patients.

In our cohort, some patients with SD still proceeded to ASCT based on their own preference when no other feasible options were available. Regarding patients with early relapse or primary refractory disease, although CAR-T is recommended by National Comprehensive Cancer Network (NCCN), many of our patients could not access CAR-T due to financial constraints, largely because CAR-T cell therapy is not reimbursed by our national health insurance, in addition to a lack of clinical trial availability, and institutional resource limitations. Therefore, ASCT was chosen as the most practical option in our real-world setting. Moreover, for patients with relapsed or refractory DLBCL who achieve CR or PR, regardless of early relapse or primary refractory disease, ASCT remains a viable option that offers comparable and even better efficacy compared with CAR-T therapy^20,21.

There are some limitations. This is a retrospective study and the number of patients who received CAR-T cell therapy or bispecific antibodies prior to ASCT is limited. Consequently, it remains uncertain whether these patients could benefit from ASCT. The efficacy of ASCT for relapsed/refractory DLBCL patients should be further evaluated in prospective and randomized controlled trials in the future. Additionally, this study only included patients who successfully proceeded to ASCT while excluding those who did not respond to salvage therapy; this may introduce a potential selection bias. Thus, future prospective studies are warranted to evaluate outcomes in the entire cohort of patients intended for transplant.

Conclusion

In summary, we observed the heterogeneity of relapsed/refractory DLBCL patients who achieved therapies response and received ASCT, and some of them might not benefit from ASCT. Prospective controlled studies should be conducted to help identify those patients who actually benefit from ASCT. More diverse treatments such as CAR-T, allogeneic hematopoietic stem cell transplantation, and bispecific antibodies should be considered for patients who do not benefit from ASCT.

Supplemental Material

sj-docx-1-cll-10.1177_09636897251397046 – Supplemental material for Do all roads lead to Rome? The heterogeneity of relapsed/refractory diffuse large B-cell lymphoma patients who achieved therapies response and received autologous stem cell transplantation in the era of new targeted drugs

Supplemental material, sj-docx-1-cll-10.1177_09636897251397046 for Do all roads lead to Rome? The heterogeneity of relapsed/refractory diffuse large B-cell lymphoma patients who achieved therapies response and received autologous stem cell transplantation in the era of new targeted drugs by Jiangtao Li, Wenxuan Huo, Yang Yang, Chunli Zhang, Fengrong Wang, Shengye Lu, Ru Feng, Yang Liu, Leqing Cao, Gaoxiang Wang, Hui Liu, Jihao Zhou, Yang Cao and Xiaodong Mo in Cell Transplantation

Footnotes

Acknowledgements

The authors appreciate Dr. Yi Xia for his help in patients’ data collection.

Authors’ Note

All authors have read and approved the manuscript, and agree that the manuscript represents honest and original work. All authors meet the criteria for authorship as per the journal’s guidelines.

ORCID iD

Wenxuan Huo

Ethical Considerations

The study adhered to the Declaration of Helsinki, study was approved by the Institutional Review Board (IRB) at Beijing Hospital Ethics Committee, with the approval numbers 2022BJYYEC-238-02 and 2016BJYYEC-018-02.

Consent to Participate

All participants or their guardians provided written informed consent before participating in the study.

Author Contributions

Xiaodong Mo, Yang Cao, Jihao Zhou, and Hui Liu were responsible for the study design. Jiangtao Li, Wenxuan Huo, Yang Yang, and Chunli Zhang collected the clinical data. Fengrong Wang, Ru Feng, Yang Liu, Gaoxiang Wang, and Leqing Cao treated the patients. Jiangtao Li and Wenxuan Huo conducted the data analysis and wrote the manuscript. Xiaodong Mo, Yang Cao, Jihao Zhou, and Hui Liu interpreted the results and provided feedback. All authors contributed to interpreting the results and reviewing the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Key Research and Development Program of China (2022YFC2502606), Peking University People’s Hospital Research and Development Funds (RZ2022-02), the Natural Science Foundation of Beijing (Z230016), Tongzhou district science and technology plan project (KJ2024CX045), and the Fundamental Research Funds for Central Universities.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Permission to Reproduce Material From Other Sources

n/a

Clinical Trial Registration (Including Trial Number)

n/a

Data Availability Statement

The dataset supporting the conclusions is available in each hospital’s clinical data repository. Individual participant data are not shared. Please contact moxiaodong@pkuph.edu.cn for original data.

Supplemental Material

Supplemental material for this article is available online.

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