Continuous R-DA-EDOCH alternated with high-dose Ara-C induces deep remission and overcomes high-risk factors in young patients with newly diagnosed mantle cell lymphoma

Continuous R-DA-EDOCH alternated with high-dose Ara-C induces deep remission and overcomes high-risk factors in young patients with newly diagnosed mantle cell lymphoma

PDF

Yi Wang¹^,², Yuting Yan¹^,², Dandan Shan¹^,², Jiawen Chen¹^,², Wei Liu¹^,², Tingyu Wang¹^,², Gang An¹^,², Weiwei Sui¹^,², Wenyang Huang¹^,², Wenjie Xiong¹^,², Huimin Liu¹^,², Qi Sun¹^,², Huijun Wang¹^,², Zhijian Xiao¹^,², Jianxiang Wang¹^,², Lugui Qiu¹^,², Dehui Zou¹^,², Shuhua Yi¹^,²

Cancer Biology & Medicine | 2025, 22(2) : 177 - 189

Less

Cancer Biology & Medicine | 2025, 22(2): 177-189

• Original Article •

Continuous R-DA-EDOCH alternated with high-dose Ara-C induces deep remission and overcomes high-risk factors in young patients with newly diagnosed mantle cell lymphoma

Full

Affiliations

¹State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China

²Tianjin Institutes of Health Science, Tianjin 301600, China

About Author:

*These authors contributed equally to this work.

Author contributions

Conceived and designed the analysis: Yi Wang, Yuting Yan, Lugui Qiu, Dehui Zou, Shuhua Yi.

Collected the data: Yi Wang, Dandan Shan, Jiawen Chen.

Contributed data or analysis tools: Yi Wang, Yuting Yan, Wei Liu, Tingyu Wang, Gang An, Weiwei Sui, Wenyang Huang, Wenjie Xiong, Huimin Liu, Qi Sun, Huijun Wang, Zhijian Xiao, Jianxiang Wang, Lugui Qiu, Dehui Zou, Shuhua Yi.

Performed the analysis: Yi Wang, Yuting Yan.

Wrote the paper: Yi Wang, Yuting Yan, Shuhua Yi.

Published: 2025-02-15 doi: 10.20892/j.issn.2095-3941.2024.0200

Outline

Abstract

Less

Objective:

Our previous studies have indicated potentially higher proliferative activity of tumor cells in Chinese patients with mantle-cell lymphoma (MCL) than those in Western. Given the success and tolerability of R-DA-EDOCH immunochemotherapy in treating aggressive B-cell lymphomas, we designed a prospective, phase 3 trial to explore the efficacy and safety of alternating R-DA-EDOCH/R-DHAP induction therapy for young patients with newly diagnosed MCL. The primary endpoint was the complete remission rate (CRR) at the end of induction (EOI).

Methods:

A total of 55 patients were enrolled. The CRR at the EOI was 89.1% [95% confidence interval (CI) 78%–96%], and the overall response rate was 98.1% (95% CI 90%–100%). Most patients with bone marrow involvement quickly attained minimal residual disease (MRD) negative status, with a 95.7% rate at the EOI.

Results:

The 3-year progression-free survival (PFS) and overall survival rates were 66.3% and 83.2%, respectively. No patients discontinued treatment because of adverse events. Univariate analysis identified pathologic morphology and TP53 mutations as risk factors for PFS. However, high tumor proliferative activity and certain cytogenetic abnormalities showed no significant adverse prognostic significance.

Conclusions:

Intensive therapy based on a high cytarabine dose and continuously administered EDOCH achieved a high MRD-negative rate and provides an optional induction choice for young patients with MCL with high-risk factors.

Key words

Mantle cell lymphoma / immunochemotherapy / high-risk factors / minimal residual disease / adverse events

Cite this Article

Yi Wang, Yuting Yan, Dandan Shan, Jiawen Chen, Wei Liu, Tingyu Wang, Gang An, Weiwei Sui, Wenyang Huang, Wenjie Xiong, Huimin Liu, Qi Sun, Huijun Wang, Zhijian Xiao, Jianxiang Wang, Lugui Qiu, Dehui Zou, Shuhua Yi. Continuous R-DA-EDOCH alternated with high-dose Ara-C induces deep remission and overcomes high-risk factors in young patients with newly diagnosed mantle cell lymphoma[J]. Cancer Biology & Medicine, 2025 , 22 (2) : 177 -189 . DOI: 10.20892/j.issn.2095-3941.2024.0200

Full Text

Less

Introduction

Less

Mantle-cell lymphoma (MCL) is a rare subtype of non-Hodgkin’s lymphoma, with a median overall survival (OS) of only 3–5 years in the era of chemotherapy¹. MCL is clinically characterized by its heterogeneity. Over the past 2 decades, substantial advances have been made in the prognosis of patients with MCL, with the advent of rituximab^2–7. Currently, both the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) guidelines advocate for multiple immunotherapy regimens containing high-dose cytarabine (Ara-C) as the first-line treatment for transplantation-eligible patients with MCL. These treatments include combinations such as RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)/R-DHAP (rituximab, dexamethasone, high-dose cytarabine, and cisplatin), R-maxi-CHOP/R-HD-Ara-C (rituximab plus high-dose cytarabine), BR (rituximab and bendamustine)/R-HD-Ara-C, R-Hyper CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone)/R-MA (high-dose methotrexate and cytarabine), and R-BAC (rituximab, bendamustine, and cytarabine)^8,9. Among these treatments, the regimen of RCHOP/R-DHAP followed by autologous stem cell transplantation (ASCT) has frequently been used in clinical studies. In observations over as many as 15 years, half the treated patients remained alive, and 40% remained in their first remission after more than a decade¹⁰. The recently proposed BR/R-HD-Ara-C regimen has also achieved high remission rates and favorable survival outcomes¹¹. Although these regimens have substantially improved the prognosis of patients with MCL, the optimal regimen remains elusive; no definitive cure is close to being available, and relapses are inevitable. Moreover, high-risk individuals, particularly those with MIPI-c, TP53, MYC abnormalities, and aggressive histology, frequently have poor prognosis¹².

With deepening understanding of the mechanism of MCL, researchers are increasingly focusing on this field, and more targeted agents have been applied clinically, thus offering promise for improving MCL outcomes (Figure 1). Recently, Bruton’s tyrosine kinase inhibitors (BTKi) have been trialed as first-line recommendations. Results from the TRIANGLE regimen trial have shown that incorporating BTKi into induction regimens enhances patient outcomes, particularly for high-risk patients¹³. However, for young patients who are transplant candidates, the traditional intensified treatment regimens already offer considerable extension in disease-free survival. Integrating BTKi might compromise patient tolerance to rigorous immunotherapy regimens, amplify the risk of infection or complications, and pose added financial burden. Precisely identifying the appropriate populations for target therapy is essential, to ensure that patients unlikely to benefit from solo immunochemotherapy receive the best tailored treatment, thus helping patients achieve maximal survival benefits at the lowest cost, and achieving personalized treatment.

Our published data have indicated that Chinese patients with MCL tend to be younger with a higher prevalence of TP53 deletion and MYC abnormalities than Western patients with MCL¹⁴. Given the efficacy and tolerability of the dose-enhanced immunochemotherapy R-DA-EDOCH regimen (dose-adjusted regimen, rituximab plus etoposide, dexamethasone, doxorubicin, cyclophosphamide, and vincristine) in patients with multiple high-risk aggressive B-cell lymphomas¹⁵ and the potentially elevated tumor cell activity in Chinese patients, we designed alternating R-DA-EDOCH/R-DHAP induction therapy as an enhanced version of the RCHOP/R-DHAP regimen for young patients with newly diagnosed MCL. We conducted a phase III study (NCT02858804) of this regimen by using the new induction procedure followed by ASCT. In this context, we examined the regimen’s efficacy and safety.

Patients and methods

Less

Patients

The “EDOCH Alternating with DHAP for Newly Diagnosed Younger MCL (BDH-MCL01)” clinical trial was registered on July 17, 2016 (registration No. NCT02858804). Trial enrollment was completed in June 2020, with an estimated enrollment of 55 patients. Eligible patients 18–65 years of age who had a confirmed diagnosis of MCL with translocation breakpoints at t (11;14) or cyclin D1 expression were enrolled. The main inclusion criteria included Ann Arbor stage II–IV and Eastern Cooperative Oncology Group performance-status score (ECOG) ≤ 1. All details regarding the inclusion and exclusion criteria are outlined in the Supplementary material.

Trial design and treatments

This open-label, nonrandomized trial was conducted in accordance with the Declaration of Helsinki. The trial protocol was approved by the institutional ethics committees (IIT2021030-EC-1), and all involved patients provided written informed consent.

During induction, patients received alternating R-DA-EDOCH/R-DHAP for 2 cycles (4 courses in total). Specific drug dosages and use are listed in the Supplementary material. Patients who achieved less than partial remission (PR) stopped the trial, whereas the other patients continued with another cycle of treatment. After the 3 cycles of inductive treatment, patients decided whether to continue ASCT consolidation therapy or another cycle of consolidation. R maintenance therapy (375 mg/m², every 3 months for as many as 8 additional doses) was recommended to all patients. Supportive care, including the use of polyethylene glycol recombinant human granulocyte stimulating factor and prophylactic anti-infective agents, was provided at the discretion of the investigator. The clinical trial process is illustrated in Figure 2.

Endpoints and assessments

The primary endpoint of this study was the complete response rate (CRR) at the end of induction (EOI). Secondary endpoints included the objective response rate (ORR) at the EOI, progression-free survival (PFS), OS, and safety and tolerability. Efficacy evaluation was performed according to the Lugano 2014 criteria with positron emission tomography-computed tomography (PET-CT) and/or computed tomography (CT) after every 2 courses of treatment. PFS was defined as the time from the initiation of therapy to progression, relapse, transformation, death, or the last visit. OS was measured from the initiation of therapy to the date of death for any reason or the last follow-up. Safety and tolerability were assessed throughout the trial and as many as 90 days after the end of treatment. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events, version 5.0.

Minimal residual disease (MRD) status was the exploratory efficacy endpoint for this trial. We conducted MRD testing on the bone marrow (if involved) at 3 time points: after the 2nd and 4th courses of treatment, as well as after the completion of induction therapy. MRD was assessed in bone marrow with eight-color multiparameter flow cytometry, as previously described¹⁶. MRD negativity was defined as a clonal malignant cell count of < 10⁻⁴ (0.01%).

Statistical analysis

Patients were continuously enrolled according to the eligibility criteria. We calculated the sample size on the basis of the primary endpoint, CRR. On the basis of the assumption of a CRR of 75% in this trial and a CRR of 55% as historical reference values², at least 50 patients were found to be required for the primary analysis. This sample size was calculated according to a test power (1-β) of 0.80, significance level (α) of 0.05 (two-tailed test), and dropout rate as 0.10. A total of 55 patients were enrolled in this study.

All efficacy endpoints were analyzed in the intention-to-treat population (defined as all patients who had undergone induction therapy), and safety was assessed in all patients who received at least one course of treatment.

Survival distributions were estimated with the Kaplan-Meier method and compared with the two-sided log-rank test. The hazard ratio and associated two-sided 95% confidence interval (CI) were calculated with a stratified Cox proportional-hazards model. Comparisons of categorical variables among subgroups were conducted with Fisher’s exact test. For continuous variables, Mann-Whitney U test was used. P values < 0.05 (two-sided) were considered statistically significant. All calculations were performed in the Statistical Package for the Social Sciences (SPSS^®) version 26.0 (IBM Corp., Armonk, NY, USA), STATA software version 15.0 (Stata Corp., College Station, TX, USA), and R version 4.0.1.

Results

Less

Patients and treatment

We enrolled 55 patients with a median age of 53 years (range: 37–65 years). The male to female ratio was 2.2:1, as detailed in Table 1. Fifty-three patients (94.6%) had advanced-stage disease (Ann Arbor stage Ⅲ–Ⅳ), and 38.2% patients exhibited B symptoms. A total of 11.5% (6/52) of cases were of blastocytic subtype and 3.8% (2/52) of cases were of pleomorphic subtype. Immunohistochemical studies revealed a Ki-67 index ≥ 30% and p53 ≥ 50% in 43.6% (17/39) and 50.0% (18/36) of patients, respectively. TP53 mutation detection was available in 42 patients, and the mutation frequency was 26.2% (11/42). Other molecular findings included MYC rearrangements/amplifications in 30.0%, 17p deletions in 18.9%, and 9p deletions in 34.1%. Notably, 16.7% of patients exhibited both TP53 mutations and 17p deletion, denoted TP53 double-allele abnormalities. Immunoglobulin heavy-chain variable region (IGHV) somatic hypermutation analysis was performed in 33 patients, 22 (66.7%) of whom had unmutated IGHV genes. Overall, 61.8% of the patients were identified to have at least one high-risk factor according to risk stratification, pathological classification, and molecular genetic abnormalities (Table 1).

All patients underwent at least 2 cycles of alternating R-DA-EDOCH/R-DHAP immunochemotherapy, and successfully completed an efficacy and safety evaluation (Figure 3). One patient dropped out because of disease progression during induction therapy. A total of 28 patients underwent ASCT consolidation therapy, and 25 patients continued another cycle of R-EDOCH/R-DHAP consolidation therapy instead of ASCT. Among those not undergoing ASCT, 13 opted for R maintenance. Baseline characteristics and risk stratification of patients with/without ASCT are listed in Table S1.

High response rate and deep remission

Among the 55 response-evaluable patients, 98.1% achieved an ORR at the end of alternating R-DA-EDOCH/R-DHAP inductive treatment (95% CI 90%–100%), and the CRR was 89.1% (95% CI 78%–96%). Calculations of CRR, ORR, and partial response rates were conducted across various subgroups, such as MIPI, MIPI-c, pathological traits, copy number variations, and crucial tumor suppressor gene mutations. No significant differences were observed in CRR and ORR among patients with various prognostic characteristics (Table 2). Patients with blastoid/pleomorphic MCL displayed a relatively unfavorable treatment response, with CRR below 80% at EOI (Table 2).

Of the 55 patients, 48 had bone marrow involvement at their initial diagnosis. Of the 48 patients, 33 (68.8%) underwent bone marrow evaluation after 2 treatment cycles. This number increased to 45 of 48 (93.8%) after 4 treatment cycles, and further increased to 46 of 48 (95.8%) at EOI. A notable majority quickly reached MRD-negative status. Specifically, the MRD-negativity rates were 51.5% after 2 treatment cycles, 93.3% after 4 cycles, and 95.7% at EOI. Impressively, by the EOI, no detectable MRD was observed among all patients achieving a complete response (CR, n = 49). Additionally, of the 5 patients with PR, MRD was undetectable in the bone marrow in 3 patients. A detailed breakdown of CR and MRD-negative rates at various stages is provided in Table S2.

Favorable tolerability

The alternating R-DA-EDOCH/R-DHAP regimen was well tolerated, and no patients discontinued treatment because of intolerable treatment-related AEs. Hematologic AEs were predominant, and 85.5% of patients experienced at least one such event. Notably, 49.1% and 58.2% of the patients exhibited grade 3–4 leukopenia and neutropenia, respectively, whereas 14.5% experienced grade 3 neutropenic fever.

Regarding non-hematologic toxicity, we observed no instances of grade 4 AEs. The most prevalent AEs were grade 1–2 nausea/vomiting (25.4%), fatigue (17.9%), and peripheral neuritis (14.5%). Regarding infection, 15 patients developed a pulmonary infection, 7 patients had upper respiratory tract infection, 4 patients had gingivitis, and 2 patients experienced conjunctivitis and presented with a grade 3 urinary tract infection. Additionally, 2 patients (3.6%) encountered grade 2 arrhythmias during treatment. Other notable events included grade 2 thrombosis in 2 patients and grade 1 bleeding in 1 patient. Detailed hematologic and non-hematologic AEs are listed in Table 3.

Improved prognosis

During a median follow-up of 48 months (range: 6–112 months), the 3-year PFS and OS rates were 66.3% and 83.2%, respectively (Figure 4). Throughout this period, 23 patients experienced disease progression. Moreover, 15 patients died: 2 because of treatment-related secondary leukemia (MCL still in CR), 1 because of cerebral infarction, 1 because of Pneumocystis carinii pneumonia during post-ASCT maintenance therapy, and the remaining 11 because of disease progression.

Sequential ASCT consolidation and/or R maintenance slightly increased the CRR but significantly extended PFS (3-year PFS rate: ASCT+R 83.6% vs. R 61.5% vs. without ASCT/R 50.0%, P = 0.009, Figure 5). However, the OS did not significantly vary across these groups. No significant difference in PFS and OS was observed between patients with (n = 34) or without (n = 9) high risk factors (PFS P = 0.735, OS P = 0.612). Univariate analysis revealed that blastoid/pleomorphic pathologic morphology (P = 0.003), TP53 mutation (P = 0.038), and TP53 double-allele events (P = 0.020) were risk factors for PFS under this therapeutic approach (Figure 6). Interestingly, factors such as high tumor proliferative activity (e.g., Ki-67 ≥ 30% and MYC abnormalities) and certain negative genetic abnormalities (e.g., deletions on chromosomes 17p and 9p) lacked statistically significant adverse prognostic implications. To further explore the effects of treatment options on the prognosis of high-risk patients, we performed a subgroup analysis of high-risk patients (with TP53 abnormalities or/and blastoid morphology). High-risk patients who completed transplantation and maintenance therapy had better prognosis than those who did not undergo transplantation or maintenance therapy (Figure S1). However, in this post-hoc analysis, some subgroups had very small sample sizes; therefore, statistical validity is lacking, and further research in larger sample sizes is necessary.

Because of the high proportion of patients with bone marrow MRD negativity after intensive treatment, only 2 patients were bone marrow MRD-positive after induction therapy. This finding might explain the absence of prognostic significance in the bone marrow MRD status (P = 0.347).

Discussion

Less

MCL is a heterogeneous disease presenting diverse pathophysiological and genetic characteristics, clinical symptoms, staging, and prognosis¹. Various clinical trials and real-world studies have assessed the potential effectiveness of various treatment approaches^{2–4,17–24}, yet a standardized and curative solution for MCL remains undefined. This prospective clinical trial underscores the efficacy and safety of the first-line induction therapy of alternating R-DA-EDOCH/R-DHAP for young patients with MCL. Impressively, most participants attained CR [CRR 89% (95% CI 78%–96%)] and MRD-negative status quickly, and showed notable tolerance. Except for pathologic morphology and TP53 aberrance, high tumor proliferative activity (such as Ki-67 ≥ 30% and MYC abnormalities) and certain other genetic abnormalities showed no significant adverse prognostic effects. Moreover, the sequential application of ASCT consolidation and/or R maintenance (P = 0.019) significantly prolonged PFS in patients with MCL.

In the era of immunochemotherapy, rituximab, high-dose cytarabine, and ASCT have emerged as the 3 cornerstones for treatment of young patients with MCL. Prior research has indicated that approximately 55% of young patients with MCL reached CR after completing alternating R-CHOP/R-DHAP induction. However, this rate is arguably insufficient for a condition known for its high aggressiveness and unfavorable outcomes. Furthermore, our previous study has indicated that Chinese patients with MCL are younger and have a higher proportion of TP53 deletion and MYC abnormalities than western patients with MCL, both of which are unfavorable prognostic indicators, thereby suggesting potentially enhanced tumor cell proliferation in this demographic¹⁴. Further analyses of Alliance/GALGB 50303 clinical trial data have indicated that R-DA-EPOCH improves PFS in intermediate-high-risk and high-risk patients with untreated diffuse large B-cell lymphoma, with relatively favorable tolerance¹⁵. Consequently, we hypothesized that alternating R-DA-EDOCH/R-DHAP would not be inferior to alternating R-CHOP/R-DHAP as the inductive therapy for eligible patients with MCL, and specific subgroups would benefit from this regimen. The CRR and the ORR at the EOI were 89% (95% CI 78%–96%) and 98% (95% CI 90%–100%), respectively, surpassing those of other immunochemotherapeutic modalities such as alternating R-CHOP/R-DHAP (55%) and R-hyper CVAD/R-MA (87%)^2,4. The patients who completed the ASCT and R maintenance showed comparable survival in our study, although the proportion of high-risk patients appeared to be greater than those in previous studies^10,25. Only 51% patients underwent ASCT consolidation and/or R maintenance in this study, partially because of COVID-19 disruptions in recent years. In alignment with findings from Le Gouill et al.⁶, the subgroup analysis affirmed that ASCT consolidation and/or R maintenance did prolong PFS in our study. However, no significant OS advantage was observed in the ASCT subgroup. The introduction of pioneering treatments after progression, such as BTKi and B-cell lymphoma-2 inhibitor (BCL2i), and/or participation in clinical trials, have largely improved post-relapse survival among patients in whom immunochemotherapy has failed.

As anticipated, alternating R-DA-EDOCH/R-DHAP induction was generally well-tolerated, with manageable rates of hematologic and infectious AEs. Grade 3–4 leukopenia and neutropenia were the most prevalent severe AEs. Nonetheless, compared with previous studies, there were limit fatal infectious events under necessary support treatment, including the utilization of granulocyte-stimulating factor and prophylactic anti-infective agents. Crucially, this regimen did not impair the successful collection of stem cells for ASCT and was suitable for patients eligible for transplantation.

One pressing challenge in contemporary lymphoma treatment is ensuring a lasting response for most patients. MRD has emerged as a critical posttreatment outcome predictor²⁶. Among patients with MCL, substantial evidence has highlighted that achieving deep remission, defined as a CR paired with MRD negativity, correlates with extended survival^11,27,28. Various methods have been used for MRD monitoring in the context of MCL, but a standard detection method remains elusive. We used a prognostic evaluation approach by integrating radiologic imaging with eight-color multiparameter flow cytometry of samples with bone marrow involvement. This approach enabled comprehensive evaluation of both nodal/extranodal lesions and bone marrow involvement. The rate of CR with bone marrow MRD negativity at the EOI reached 88.7%, a value higher than those in prior studies. Compared with other studies, this result indicated deeper remission and better status for the following therapy. In particular, the longitudinal data also indicated rapid remission in our cohort, thereby demonstrating the potency of the regimen.

Given the limited sample size of our cohort, we did not perform further multivariate prognostic analysis. In our univariate prognostic analysis, traditionary risk factors^1,12 such as MIPI, 17p deletion and 9p deletion did not significantly influence survival. Notably, risk factors associated with tumor proliferative activity, such as Ki-67 ≥ 30% and MYC abnormalities, exhibited no marked prognostic significance, as expected. The CRR and MRD-negative rate were relatively high in these high-risk patients. These results suggested that R-DA-EDOCH/R-DHAP therapy was an effective induction regimen in patients with high proliferative activity. However, this intensive treatment did not work well in patients with blastoid/pleomorphic pathologic morphology and patients with TP53 mutation and/or TP53 double-allele events. Together with results from other studies, our findings highlighted that immunochemotherapy alone might not fully overcome the adverse prognostic effects of pathologic morphology and TP53 aberrance^12,29. Over the past decade, the therapeutic landscape for MCL has considerably evolved. Targeted agents, such as immunomodulatory drugs (e.g., lenalidomide), BTKi, and BCL2i, have shown remarkable efficacy in patients with relapsed/refractory status and are now options in first line therapy, particularly for high-risk patients with MCL²⁹. The key molecular mechanisms and rationale for use of targeted agents in MCL are illustrated in Figure 1. Encouragingly, the subgroup analysis of the ZUMA-2 clinical trial indicated comparable ORRs for patients regardless of blastoid morphology and TP53 mutation³⁰. We eagerly anticipate further studies to provide deeper insights into high-risk MCL and to enhance the survival prospects of these patients.

Conclusions

Less

In summary, alternating R-DA-EDOCH/R-DHAP inductive therapy showed impressive efficacy and favorable tolerability in young untreated patients with MCL in this prospective study. Under intensive therapy, patients showed a significant increase in the rate of deep remission and MRD-negative status. Intensive therapy based on a high dose of cytarabine and continuously administered EDOCH may partially overcome the adverse prognostic effects of high-risk factors such as high MIPI risk, high Ki-67, and MYC abnormalities. However, this treatment cannot fully overcome the negative effects of blastoid pathological subtypes and TP53 mutations. Combination therapy with targeted drugs is necessary to provide patients with additional survival benefits. The alternating R-DA-EDOCH/R-DHAP regimen presents a compelling induction choice for young patients with MCL, particularly for those with high tumor proliferative activity.

Funding

Less

This study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82200215, 82170193, and 82370197) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (Grant No. 2022-I2M-1-002).

References

Less

Jain P,Wang ML.Mantle cell lymphoma in 2022 – a comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments.Am J Hematol.2022; 97: 638–56.

Pott C,Hoster E,Beldjord K,Macintyre EA,Böttcher S,Asnafi V, et al.R-CHOP/R-DHAP compared to R-CHOP induction followed by high dose therapy with autologous stem cell transplantation induces higher rates of molecular remission in MCL: results of the MCL younger intergroup trial of the European MCL network.Blood.2010; 116: 965.

Delarue R,Haioun C,Ribrag V,Brice P,Delmer A,Tilly H, et al.CHOP and DHAP plus rituximab followed by autologous stem cell transplantation in mantle cell lymphoma: a phase 2 study from the Groupe d’Etude des Lymphomes de l’Adulte.Blood.2013; 121: 48–53.

Chihara D,Cheah CY,Westin JR,Fayad LE,Rodriguez MA,Hagemeister FB, et al.Rituximab plus hyper-CVAD alternating with MTX/Ara-C in patients with newly diagnosed mantle cell lymphoma: 15-year follow-up of a phase II study from the MD Anderson Cancer Center.Br J Haematol.2016; 172: 80–8.

Hoster E,Rosenwald A,Berger F,Bernd HW,Hartmann S,Loddenkemper C, et al.Prognostic value of Ki-67 index, cytology, and growth pattern in mantle-cell lymphoma: results from randomized trials of the European mantle cell lymphoma network.J Clin Oncol.2016; 34: 1386–94.

Le Gouill S,Thieblemont C,Oberic L,Moreau A,Bouabdallah K,Dartigeas C, et al.Rituximab after autologous stem-cell transplantation in mantle-cell lymphoma.N Engl J Med.2017; 377: 1250–60.

Yamshon S,Martin P,Shah B,Schuster SJ,Christos PJ,Rodriguez A, et al.Initial treatment with lenalidomide plus rituximab for mantle cell lymphoma (MCL): 7-year analysis from a multi-center phase II study.Blood.2020; 136: 45–6.

NCCN.National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: B-Cell Lymphomas.2023. Version 6.

Dreyling M,Thieblemont C,Gallamini A,Arcaini L,Campo E,Hermine O, et al.ESMO consensus conferences: guidelines on malignant lymphoma. Part 2: marginal zone lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma.Ann Oncol.2013; 24: 857–77.

10.

Eskelund CW,Kolstad A,Jerkeman M,Räty R,Laurell A,Eloranta S, et al.15-year follow-up of the second Nordic mantle cell lymphoma trial (MCL2): prolonged remissions without survival plateau.Br J Haematol.2016; 175: 410–8.

11.

Merryman RW,Edwin N,Redd R,Bsat J,Chase M,LaCasce A, et al.Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma.Blood Adv.2020; 4: 858–67.

12.

Jain P,Dreyling M,Seymour JF,Wang M.High-risk mantle cell lymphoma: definition, current challenges, and management.J Clin Oncol.2020; 38: 4302–16.

13.

Dreyling M,Doorduijn JK,Gine E,Jerkeman M,Walewski J,Hutchings M, et al.Efficacy and safety of ibrutinib combined with standard first-line treatment or as substitute for autologous stem cell transplantation in younger patients with mantle cell lymphoma: results from the randomized triangle trial by the European MCL network.Blood.2022; 140: 1–3.

14.

Yi S,Zou D,Li C,Zhong S,Chen W,Li Z, et al.High incidence of MYC and BCL2 abnormalities in mantle cell lymphoma, although only MYC abnormality predicts poor survival.Oncotarget.2015; 6: 42362–71.

15.

Bartlett NL,Wilson WH,Jung SH,Hsi ED,Maurer MJ,Pederson LD, et al.Dose-adjusted EPOCH-R compared with R-CHOP as frontline therapy for diffuse large B-cell lymphoma: clinical outcomes of the phase III intergroup trial alliance/CALGB 50303.J Clin Oncol.2019; 37: 1790–9.

16.

Lyu R,Wang T,Wang Y,Xiong W,Wang H,Yan Y, et al.Undetectable minimal residual disease is an independent prognostic factor in splenic marginal zone lymphoma.Br J Haematol.2021; 194: 862–9.

17.

Gianni AM,Magni M,Martelli M,Di Nicola M,Carlo-Stella C,Pilotti S, et al.Long-term remission in mantle cell lymphoma following high-dose sequential chemotherapy and in vivo rituximab-purged stem cell autografting (R-HDS regimen).Blood.2003; 102: 749–55.

18.

Dreyling M,Lenz G,Hoster E,Van Hoof A,Gisselbrecht C,Schmits R, et al.Early consolidation by myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission significantly prolongs progression-free survival in mantle-cell lymphoma: results of a prospective randomized trial of the European MCL network.Blood.2005; 105: 2677–84.

19.

Lenz G,Dreyling M,Hoster E,Wörmann B,Dührsen U,Metzner B, et al.Immunochemotherapy with rituximab and cyclophosphamide, doxorubicin, vincristine, and prednisone significantly improves response and time to treatment failure, but not long-term outcome in patients with previously untreated mantle cell lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group (GLSG).J Clin Oncol.2005; 23: 1984–92.

20.

Romaguera JE,Fayad L,Rodriguez MA,Broglio KR,Hagemeister FB,Pro B, et al.High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine.J Clin Oncol.2005; 23: 7013–23.

21.

Geisler CH,Kolstad A,Laurell A,Andersen NS,Pedersen LB,Jerkeman M, et al.Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group.Blood.2008; 112: 2687–93.

22.

Hermine O,Hoster E,Walewski J,Ribrag V,Brousse N,Thieblemont C, et al.Alternating courses of 3x CHOP and 3x DHAP plus Rituximab followed by a high dose ARA-C containing myeloablative regimen and autologous stem cell transplantation (ASCT) is superior to 6 courses CHOP plus Rituximab followed by myeloablative radiochemotherapy and ASCT in mantle cell lymphoma: results of the MCL Younger Trial of the European mantle cell lymphoma network (MCL net).Blood.2010; 116: 110.

23.

Geisler CH,Kolstad A,Laurell A,Jerkeman M,Räty R,Andersen NS, et al.Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur.Br J Haematol.2012; 158: 355–62.

24.

Delfau-Larue MH,Klapper W,Berger F,Jardin F,Briere J,Salles G, et al.High-dose cytarabine does not overcome the adverse prognostic value of CDKN2A and TP53 deletions in mantle cell lymphoma.Blood.2015; 126: 604–11.

25.

Hermine O,Jiang L,Walewski J,Bosly A,Thieblemont C,Szymczyk M, et al.High-dose cytarabine and autologous stem-cell transplantation in mantle cell lymphoma: long-term follow-up of the randomized mantle cell lymphoma younger trial of the European mantle cell lymphoma network.J Clin Oncol.2023; 41: 479–84.

26.

Ladetto M,Tavarozzi R,Pott C.Minimal residual disease in mantle cell lymphoma: methods and clinical significance.Hematol Oncol Clin North Am.2020; 34: 887–901.

27.

Callanan MB,Delfau M-H,Macintyre E,Thieblemont C,Oberic L,Gyan E, et al.Predictive power of early, sequential MRD monitoring in peripheral blood and bone marrow in patients with mantle cell lymphoma following autologous stem cell transplantation with or without rituximab maintenance; interim results from the LyMa-MRD project, conducted on behalf of the Lysa Group.Blood.2015; 126: 338.

28.

Kolstad A,Pedersen LB,Eskelund CW,Husby S,Grønbæk K,Jerkeman M, et al.Molecular monitoring after autologous stem cell transplantation and preemptive rituximab treatment of molecular relapse; results from the Nordic mantle cell lymphoma studies (MCL2 and MCL3) with median follow-up of 8.5 years.Biol Blood Marrow Transplant.2017; 23: 428–35.

29.

Kumar A,Eyre TA,Lewis KL,Thompson MC,Cheah CY.New directions for mantle cell lymphoma in 2022.Am Soc Clin Oncol Educ Book.2022; 42: 1–15.

30.

Wang M,Munoz J,Goy A,Locke FL,Jacobson CA,Hill BT, et al.Outcomes with KTE-X19 in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) in ZUMA-2 who had progression of disease within 24 months of diagnosis (POD24).J Clin Oncol.2021; 39: 7547–7.

Appendix

Less

Year 2025 volume 22 Issue 2

PDF

Cite this Article

BibTeX

Article Info

doi: 10.20892/j.issn.2095-3941.2024.0200

Receive Date：2024-06-01
Online Date：2026-11-06
Published：2025-02-15

Article Data

Affiliations

History

Received：2024-06-01
Accepted：2025-01-07

Funding

This study was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82200215, 82170193, and 82370197) and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (Grant No. 2022-I2M-1-002).

Affiliations

²Tianjin Institutes of Health Science, Tianjin 301600, China

Corresponding:

Correspondence to: Dehui Zou and Shuhua Yi, E-mail: zoudehui@ihcams.ac.cn and yishuhua@ihcams.ac.cn

References

Share

https://castjournals.cast.org.cn/joweb/cbm/EN/10.20892/j.issn.2095-3941.2024.0200

Share to

Scan QR to access full text

Cite this article

BibTeX

Citations

表12种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

关闭全屏

BibTeX
EndNote
RefWorks
TxT

Table 1 Baseline characteristics and risk stratification

Characteristics	n/N (%)
Sex
Male	38/55 (69.1)
Ann Arbor
Ⅱ	3/55 (5.4)
Ⅲ	4/55 (7.3)
Ⅳ	48/55 (87.3)
B symptoms	21/55 (38.2)
Pathological type
Blastoid	6/52 (11.5)
Pleomorphic	2/52 (3.8)
Classic	44/52 (84.7)
Immunohistochemistry
Ki-67 ≥ 30%	17/39 (43.6)
p53 ≥ 50%	18/36 (50.0)
Karyotype
Complex	9/46 (19.6)
IGHV
Unmutated	22/33 (66.7)
FISH
17p deletion	10/53 (18.9)
9p deletion	14/41 (34.1)
17p deletion and 9p deletion	5/41 (12.2)
MYC translocation/amplification	9/30 (30.0)
Gene mutation
TP53	11/42 (26.2)
TP53 and 17p-	7/42 (16.7)
CDKN2A	0/37 (0.0)
MIPI
Low	32/55 (58.2)
Intermediate	11/55 (20.0)
High	12/55 (21.8)
MIPI-c
Low	19/39 (48.7)
Low-intermediate	12/39 (30.7)
Intermediate-high	4/39 (10.3)
High	4/39 (10.3)
HR*	34/55 (61.8)

HR*, including at least one high-risk factor as follows: (1) MIPI-high; (2) MIPI-c-high; (3) blastoid/pleomorphic pathological type; (4) TP53 mutation; (5) 17p deletion; (6) immunohistochemistry p53 ≥ 50%; (7) 9p deletion; (8) MYC translocation/amplification; (9) complex karyotype. IGHV, immunoglobulin heavy-chain variable region.

Table 2 EOI response rates among response-evaluable patients in the indicated subgroups

Group	ORR, n/N (%) (95% CI)	CRR, n/N (%) (95% CI)	PRR, n/N (%) (95% CI)
Overall	54/55 (98) (90–100)	49/55 (89) (78–96)	5/55 (9) (3–20)
MIPI-low	31/32 (97) (84–100)	28/32 (88) (71–97)	3/32 (9) (2–25)
MIPI-intermediate	11/11 (100) (72–100)	10/11 (91) (59–100)	1/11 (9) (0–41)
MIPI-high	12/12 (100) (74–100)	11/12 (92) (62–100)	1/12 (8) (0–39)
Defined high risk	34/34 (100) (90–100)	32/34 (94) (80–99)	2/34 (6) (1–20)
Classic	43/44 (98) (88–100)	40/44 (91) (78–98)	3/44 (7) (1–19)
Blastoid/pleomorphic	8/8 (100) (63–100)	6/8 (75) (35–97)	2/8 (25) (3–65)
Ki-67 < 30%	21/22 (95) (77–100)	20/22 (91) (71–99)	1/22 (4) (0–23)
Ki-67 ≥ 30%	17/17 (100) (81–100)	14/17 (82) (57–96)	3/17 (18) (4–43)
IHC P53 < 50%	18/18 (100) (83–100)	16/18 (89) (65–99)	2/18 (11) (1–35)
IHC P53 ≥ 50%	18/18 (100) (82–100)	16/18 (89) (65–99)	2/18 (11) (1–35)
17p-	10/10 (100) (69–100)	9/10 (90) (56–100)	1/10 (10) (0–45)
Without 17p-	41/42 (98) (87–100)	37/42 (88) (74–96)	4/42 (10) (3–23)
9p-	14/14 (100) (77–100)	12/14 (86) (57–98)	2/14 (14) (2–43)
Without 9p-	26/27 (96) (81–100)	24/27 (89) (71–98)	2/27 (7) (1–24)
MYC abnormalities	10/10 (100) (69–100)	10/10 (100) (69–100)	0/10 (0) (0–0)
Without MYC abnormalities	19/20 (95) (75–100)	15/20 (75) (51–91)	4/20 (20) (6–44)
Complex karyotype	9/9 (100) (66–100)	9/9 (100) (66–100)	0/9 (0) (0–0)
Without complex karyotype	36/37 (97) (86–100)	34/37 (92) (78–98)	2/37 (5) (1–18)
TP53 mutation	11/11 (100) (72–100)	9/11 (82) (48–98)	2/11 (18) (2–52)
Without TP53 mutation	30/31 (97) (83–100)	27/31 (87) (70–96)	3/31 (10) (2–26)
IGHV-unmutated	22/22 (100) (85–100)	18/22 (82) (60–95)	4/22 (18) (5–40)
IGHV-mutated	10/11 (91) (59–100)	10/11 (91) (59–100)	0/10 (0) (0–0)

EOI, end of induction; ORR, objective response rate; CRR, complete response rate; PRR, partial remission rate; 95% CI, 95% confidence interval; MIPI, Mantle cell lymphoma International Prognostic Index; IHC, immunohistochemistry; 17p-, 17p deletion; 9p-, 9p deletion; MYC abnormalities, MYC translocation and/or amplification; IGHV, immunoglobulin heavy-chain variable region.

Table 3 Hematologic and non-hematologic adverse events

Categories	SAEs (%)	Grade 4 (%)	Grade 3 (%)	Grade 2 (%)	Grade 1 (%)
Leukocytopenia	27 (49.1)	13 (23.6)	14 (25.5)	13 (23.6)	6 (10.9)
Neutrocytopenia	32 (58.2)	19 (34.6)	13 (23.6)	8 (14.5)	3 (5.5)
Anemia	4 (7.3)	0 (0.0)	4 (7.3)	24 (43.6)	4 (7.3)
Thrombocytopenia	14 (25.5)	9 (16.4)	5 (9.1)	5 (9.1)	4 (7.3)
Febrile neutropenia	8 (14.5)	0 (0.0)	8 (14.5)	0 (0.0)	0 (0.0)
Fatigue	0 (0.0)	0 (0.0)	0 (0.0)	6 (10.6)	4 (7.3)
Nausea/vomiting	0 (0.0)	0 (0.0)	0 (0.0)	7 (12.7)	7 (12.7)
Abdominal distension/pain	0 (0.0)	0 (0.0)	0 (0.0)	2 (3.6)	1 (1.8)
Diarrhea	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.8)	3 (5.5)
Constipation	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.8)
Hyperglycemia	2 (3.6)	0 (0.0)	2 (3.6)	3 (5.5)	3 (5.5)
Hypokalemia	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	4 (7.3)
Elevated creatinine	0 (0.0)	0 (0.0)	0 (0.0)	3 (5.5)	1 (1.8)
Upper respiratory infection	1 (1.8)	0 (0.0)	1 (1.8)	6 (10.6)	0 (0.0)
Pulmonary infection	13 (23.6)	0 (0.0)	13 (23.6)	2 (3.6)	0 (0.0)
Urinary system infection	1 (1.8)	0 (0.0)	1 (1.8)	0 (0.0)	0 (0.0)
Gingivitis	1 (1.8)	0 (0.0)	1 (1.8)	3 (5.5)	0 (0.0)
Conjunctivitis	0 (0.0)	0 (0.0)	0 (0.0)	2 (3.6)	0 (0.0)
Epistaxis	0 (0.0)	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.8)
Thrombus	0 (0.0)	0 (0.0)	0 (0.0)	2 (3.6)	0 (0.0)
Arrhythmia	0 (0.0)	0 (0.0)	0 (0.0)	2 (3.6)	0 (0.0)
Infusion reactions	0 (0.0)	0 (0.0)	0 (0.0)	2 (3.6)	0 (0.0)
Peripheral neuritis	0 (0.0)	0 (0.0)	0 (0.0)	1 (1.8)	7 (12.7)

Figure 1 Key molecular mechanisms/rationales for targeted agents in mantle cell lymphoma (MCL). In MCL, sustained activation of the B-cell receptor complex results in cellular growth and survival through multiple downstream signaling pathways. This figure shows the main signaling pathways and molecules involved in B cell receptor activation, such as Btk and NF-κB. Arrows point to downstream signaling molecules or their roles. White boxes indicate novel therapies that inhibit critical elements of this signaling pathway. Akt, protein kinase B; Bak, B-cell lymphoma-2 homologous antagonist killer; Bax, B-cell lymphoma-2–associated X protein; Bcl2, B-cell lymphoma protein-2; Btk, Bruton’s tyrosine kinase; CRBN, cereblon; DC, dendritic cell; IgH, immunoglobulin heavy chain; IL-2, interleukin-2; IKZF3, Aiolos; IZKF1, Ikaros; Lyn, Src-family kinase p53/56Lyn; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor-κB; PI3K, phosphatidylinositol 3-kinase; PKCβ, protein kinase Cβ; PLCγ2, phospholipase Cγ2; Syk, spleen tyrosine kinase; Th, T-helper cell; Treg, T-regulatory cell.

Figure 2 Clinical trial diagram. MCL, mantle cell lymphoma; ECOG, Eastern Cooperative Oncology Group performance-status score; ASCT, autologous stem cell transplantation; R maintain, rituximab maintenance treatment; CRR, complete response rate; EOI, end of induction; ORR, objective response rate; PFS, progression-free survival; OS, overall survival.

Figure 3 Patient flow. PD, progressive disease; ASCT, autologous stem cell transplantation; R maintain, rituximab maintenance treatment.

Figure 4 PFS (A) and OS (B) of the entire cohort. PFS, progression-free survival; OS, overall survival.

Figure 5 Response rates (A), PFS (B), and OS (C) for the indicated treatment subgroups. ASCT + R maintain, patients received both autologous stem cell transplantation and rituximab maintenance treatment; R maintain along, patients received only rituximab maintenance treatment after induction therapy; no ASCT or maintain, patients received neither autologous stem cell transplantation nor rituximab maintenance treatment; PFS, progression-free survival; OS, overall survival.

Figure 6 Univariate analysis of PFS. PFS, progression-free survival; MIPI, Mantle cell lymphoma International Prognostic Index; IHC, immunohistochemistry; 17p-, 17p deletion; 9p-, 9p deletion; MYC abnormalities, MYC translocation and/or amplification; IGHV, immunoglobulin heavy-chain variable region; ASCT + R maintain, patients received both autologous stem cell transplantation and rituximab maintenance treatment; R maintain along, patients only received rituximab maintenance treatment after induction therapy; no ASCT or maintain, patients received neither autologous stem cell transplantation nor rituximab maintenance treatment; MRD, minimal residual disease; EOI, end of induction.

Articles: Latest Articles; Most Read; Collections

Updates: Events; News; Multimedia

About: About Us

Contact

No. 86 Xueyuan South Road, Haidian District, Beijing

100081

010-62662699(Operation and Technical Support)

qkjq@cast.org.cn

Copyright © 2025 China Association for Science and Technology. All rights reserved. For all open access content, the relevant licensing terms apply.
Sponsored by the Office of the Leading Group for Cybersecurity and Informatization of CAST, and supported by Science and Technology Review Publishing House