Clinical and demographic characteristics
A total of 693 mantle cell lymphoma patients with integrated clinical, treatment, and follow-up data from 19 centers in China were included in this study. 534 patients were male (77.1%), with a male-to-female ratio of 3.36:1. The median age at diagnosis was 60.0 years (range, 25-88 years). Four hundred and seventy-eight patients (69.0%) were younger than 65 years at diagnosis, and two hundred and fifteen patients (31.0 %) were older than 65 years. Clinical and demographic characteristics of the younger and older patients are summarized in Table 1. Compared with the younger cohort, older patients were more likely to have extranodal organs(P=0.003), bone marrow involvement(P=0.004), and high level of LDH (P=0.044). According to MIPI and MIPI-c prognostic scoring index, the proportion of high-risk group and high/high-intermediate risk group in elderly patients is more higher, 33.5% vs 11.3% and 58.2% vs 28.5%, respectively.
At the same time, we collected the clinical manifestations of patients at diagnosis. The main symptoms were as follows: superficial tumor or mass (62.6%), abdominal pain or distension (14.1%), dysphagia (7.8%); the secondly symptoms were fatigue, fever, abnormal hemogram, and hepatosplenomegaly.
First-line and maintenance treatment
In our study, all 693 patients received chemotherapy as first-line treatment. The therapeutic schedule is not completely unified. Among of them, the most frequently regimen is CHOP/CHOP-like±R with 312 patients(45.0%) used, 222 patients（32.0%）were treated with high-dose cytarabine, 154 patients(22.2%) received CHOP / DHAP±R regimen, and 45 patients (6.5%) received dose adjusted hyper CVAD±R regimen, and 23 patients (3.3%) received high cytarabine + R regimen , 44 patients (6.3%) received VR-CAP regimen,30 patients (4.3%) received BR regimen, 55 patients(7.9%) initially chose chemo-free regimen including IR / R2 / IR2,and other less used initial treatments included R-EPOCH (n = 17, 2.5%) and FC / FCM±R regimen (n = 13, 1.9%)(Figure2). Despite the high proportion of young patients, only 80 patients (11.5%) received autologous hematopoietic stem cell transplantation as consolidation therapy after chemotherapy remission.
In this study, 309 patients (44.6%) received maintenance therapy as consolidation treatment after initial treatment. Among them, 151 patients (21.8%) received rituximab maintenance regimen, 43 patients (6.2%) received lenalidomide maintenance regimen, 47 patients (6.8%) received ibrutinib maintenance therapy, and 67 patients (9.7%) received IR / R2 regimen as the maintenance therapy.
Response data and relapse/refractory treatment
In the initial treatment, the overall response rate (ORR) was 85.0%, of which complete remission (CR) rate was 46.6%, partial remission (PR) was 38.4%. Furthermore, the study compared the efficiency between different first-line treatment regimens. The results showed that the ORR rate and CR rate in high-dose cytarabine regimen were better than other non high-intensity treatment regimens, 92.4% vs 81.5% and 68.6% vs 36.2%, respectively. There was statistical difference between the two groups (P=0.000, P=0.000).
In the follow-up time, 409 (59.0%) patients were relapsed and refractory, of which 104 patients (15.0%) were refractory, 305 patients (44.0%) relapsed after remission. We further analyzed the correlation between clinical parameters and whether patients were relapsed and refractory. Binary logistic regression analysis showed that age≥65 years old, stage III /IV by Ann Abor staging, B symptoms, high-risk group according to MIPI-c and MIPI index, elevated LDH level and initial treatment without high-dose Ara C and without maintenance treatment were the related factors to replased/refractory in MCL patients. Multiple logistic regression analysis suggested that elevated LDH level and initial treatment without high-dose Ara C and without maintenance treatment were independent related factors in relapse/refractory MCL.
Among them, 360 available patients received treatment including salvage chemotherapy, new drug therapy and BR regimen chemotherapy. The new drugs mainly included lenalidomide, ibrutinib and bortezomib, which are used alone or in combination with other drugs.125 patients only received salvage chemotherapy, the ORR was 29.6 % and CR was 7.2%. 205 patients received new drugs single or combined treatment with ORR 64.4% and CR16.1%. 30 patients were treated with BR regimen, and the ORR was 53.3% and CR was 23.3% respectively.
Survival and prognostic factors
During the follow-up to June 2021, 222 patients (32.0%) had died. The 3-year and 5-year PFS of the global series was 51.5% and 30.9 %，the 3-year and 5-year OS of the global series was 78.6% and 65.0 %, respectively (Figure3). In univariable analysis, we analyzed the common variables, which including age, gender, tumor proliferation index, pathological type, stage, B symptoms, LDH level, ECOG, extranodal organ involvement, different extranodal involvement sites, MIPI index, and MIPI-c index. At the same time, we also analyzed the treatment related factors, including initial treatment regimens, autologous hematopoietic stem cell transplantation, initial therapeutic efficacy, relapsed/refractory and treatment lines.
The result showed that age ≥ 65 years, ki67≥30%, ki67≥50%, stage Ⅲ-Ⅳ, B symptoms, LDH elevated, extranodal organ involvement, spleen involvement, bone marrow involvement, high-risk group according to MIPI/MIPI-c index, high-dose cytarabine in first-line therapy, auto-ASCT, maintenance treatment, CR/PR in initial treatment were significantly correlated with worse PFS in univariable analysis. Except of the above factors ,year of diagnosis, pathological subtype and relapsed/ refractory state were associated with poor OS in univariable analysis.
Low-intermediate/low risk group according to MIPI-c, high-dose cytarabine regimen, auto-ASCT as consolidation therapy, CR/PR after initial treatment and maintenance treatment were associated with better PFS on multivariable analyses (Table2, Figure4). Meanwhile, ki67≥50%,B symtoms, high-intermediate/high risk group according to MIPI-c, without high-dose cytarabine, lack of maintenance treatment, CR/PR after initial treatment and relapse/refractory state were the independent prognostic factors for OS (Table2, Figure4).
In our cohort, we compared PFS and OS according to different induction regimens. There were significant differences in PFS and OS between high-dose cytarabine-containing regimen group and non-intensified chemotherapy group, and the 5 year-PFS and OS were 48.9% vs 24.0% and 81.7% vs 57.0%, respectively (p<0.001, p<0.001, Figure5). Among the young patients, 191 patients chose the treatment regimen containing high-dose cytarabine in the initial treatment. As the same as the overall population, the high-dose cytarabine treatment group has the survival advantage in the young cohort, with the 5 year-PFS and OS were 50.4% vs 27.3% and 83.2% vs 67.5%, respectively (p<0.001, p<0.001, Figure5). Further, we compared the different cytarabine-containing regimens in the young cohort, 122 young patients received CHOP / DHAP±R regimen, and 42 patients received dose adjusted hyper CVAD±R regimen, and 22 patients received R- high cytarabine regimen. There was no significant difference in PFS and OS between different high-dose cytarabine regimens (p=0.144, p=0.494 , Figure5).
55 patients (7.9%) initially chose chemo-free regimen including IR / R2 / IR2 due to unfit condition or refusing chemotherapy, the ORR rate and CR rate were 81.8% and 23.6% in this group, the 5-year PFS and 5-year OS was 34.5% and 57.1%, respectively. There was no significant difference in PFS compared with chemo-regimens (p=0.359), however, chemo-regimens was better than chemo-free group in OS(p=0.003), which may due to the unfit state and short follow-up time in chemo-free cohort.
Survival was compared in patients who were treated with Auto-SCT (N=80) and non-ASCT as consolidation therapy (Figure6). 5-year PFS rates were 68.8% vs 25.3% (p<0.001) and 5-year OS rates were 87.3 %vs 61.7% (p<0.001) respectively. We further compared PFS and OS according to induction regimens with or without Auto-SCT. Non-intensified induction regimens with Auto-SCT(N=29) , and without Auto-SCT(N=441), 5 -year PFS and 5-year OS rates were 66.0% vs 20.3%((p<0.001), 78.1% vs 55.4% (p=0.012) respectively(Figure6). In high-dose cytarabine induction regimens with Auto-SCT(N=51) and without Auto-SCT (N=172) groups, 5-year PFS and 5-year OS rates were 68.5% vs 42.1%(p=0.004), 90.4% vs 78.8% (p=0.11) respectively (Figure6).
Maintenance regimen in our research was not consistent. Once again, we further compared PFS and OS with or without MR. The 5-years PFS and 5-years OS rates in the maintenance regimen and non-maintenance regimen group were 53.6 % vs 17.2% ,82.7% vs 52.9% respectively. There were significant differences between the two groups (p<0.001, p<0.001). However, there was no significant difference in PFS and OS between different maintenance therapy including rituximab, lenalidomide, ibrutinib and IR/R2 regimens (p=0.520 p=0.270) (Figure 7).
The Kaplan–Meier method was applied to estimate time-to-event outcomes (OS-2）and comparisons between treatment groups were performed in our cohort. Compared with salvage chemotherapy, new drugs treatment and BR regimen have obvious survival advantages and the median OS-2 for patients with new drugs treatment and BR regimen were 21.0 months and 23.0 months respectively, the median OS-2 of patients treated with salvage chemotherapy was 16.0m (p<0.001 ,Figure 7).
During the follow-up of this study, 34 patients (4.90%) complicated with or developed a secondary malignancy. The most common secondary malignancy is lung cancer (N=7), the second is hematological malignancies, including AML, ALL, MDS and DLBCL(N=6), then followed by breast cancer(N=4), prostate cancer(N=3) gastric cancer (N=3) and colon cancer (N=3). (Table3)