SHORT COMMUNICATION
Mantle cell lymphoma (MCL) is an indolent non-Hodgkin lymphoma (NHL) derived from the mantle zone of lymph nodes and is characterized by over-expression of cyclin D1 associated with chromosomal translocation t(11;14)(q12;q32).1 Although the median survival of patients with MCL has been reported as three-to-five years, MCL is a heterogeneous disease category comprising leukemic non-nodal type with a slow clinical course of more than 10 years, rapidly progressive pleomorphic variants, and blastoid variants.2 TP53 genetic abnormalities and high Ki67 index have been reported as poor prognostic factors of MCL.3 The simplified MCL International Prognostic Index (MIPI) is a widely used prognostic scoring system for MCL.4 Progression of disease within 24 months (POD24) has emerged as an important prognostic marker for overall survival (OS) in several types of B-cell lymphoma, and a previous study has suggested the effect of POD24 on survival in MCL.5,6 High-dose cytarabine-containing chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard therapy for young patients.7 R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone),8 BR (bendamustine and rituximab),9 and VR-CAP (rituximab, cyclophosphamide, doxorubicin, bortezomib, and prednisone)10 have been treatment options as first-line therapies for patients ineligible for ASCT. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, was approved in Japan for relapsed/refractory MCL in December 2016, and has become a key drug in its treatment.11 Numerous real-world MCL datasets have recently been reported using an administrative database with a large cohort.12 However, due to the rarity and heterogeneity of MCL, there have not been enough reports about treatment outcomes following recent treatment strategies.
Here, we conducted a retrospective observational study to clarify prognostic factors of MCL in real-world practice. Patients with previously untreated MCL were recruited between 2008 and 2022 at two hospitals in Oita, Japan (Oita Prefectural Hospital and Oita Kouseiren Tsurumi Hospital). A total of 41 patients were diagnosed consecutively and enrolled in the study. Response was determined according to the Lugano classification13 by computed tomography (CT) or 18F-fluorodeoxyglucose positron emission tomography/CT and overall response was defined as achievement of partial response (PR) or complete response (CR). Adverse events were evaluated by CTCAE Ver5.0. Survival probabilities were estimated by the Kaplan–Meier method. OS was calculated from the start date of first-line treatment to the date of death or last follow-up. Progression-free survival (PFS) was calculated from the start date of first-line treatment to the date of relapse, or death from any cause. Factors affecting OS and PFS were analyzed using the log-rank test in univariate analyses and the Cox proportional hazard model in multivariate analyses. POD24 was calculated from the date of diagnosis to the date of progression or death due to disease progression that occurred within 24 months. The cumulative incidence of POD24 was analyzed using Gray’s test in univariate analyses and the Fine‒Gray hazard model in multivariate analyses, and the competing event was deaths without disease progression. OS was compared between patients with and without POD24. The following variables were considered in the analyses of prognostic factors: age (<70 years vs. ≥70 years), sex (male vs. female), performance status (PS) (0–1 vs. 2–4), white blood counts (WBC) (<9,000 /µL vs. ≥9,000 /µL), serum lactate dehydrogenase (LDH) (<220 U/L vs. ≥220 U/L), soluble interleukin-2 receptor (sIL-2R) (<1,700 U/mL vs. ≥1,700 U/mL), blastoid variant (non-blastoid variant vs. blastoid variant), Ki67 index (<30% vs. ≥30%), and clinical stage (limited vs. advanced). Cutoff values of WBC, serum LDH were according to the upper normal range. In the receiver-operator characteristics (ROC) curve of sIL-2R for OS, the point with the minimum distance from the upper left corner was 1,749 U/mL (sensitivity was 61.9% and specificity was 65.0%), and the area under the ROC curve = 0.652 (95% confidence interval (CI): 0.482–0.823). In consideration of the median sIL-2 level and the ROC curve, we used a sIL-2R of 1,700 U/mL as the cutoff value. Variables with P values of <0.1 in univariate analyses were entered into multivariate analyses. For all analyses, P values were two sided, and P < 0.05 was considered statistically significant. All statistical analyses were performed with EZR software.14 This study was approved by the ethics review board of Oita Prefectural Hospital, and patients’ informed consent was obtained in the form of opt-out on the website.
Median age was 70 years (range, 48–86 years), and 31/41 patients were male (75.6%). The median PS, WBC, serum LDH, and sIL-2R levels were 0 (range, 0–3), 5,550 /µL (range, 2,290–56,780 /µL), 205 U/L (range, 148–1,876 U/L), and 1,748 U/mL (range, 221–19,188 U/mL), respectively. The pathological diagnosis was blastoid variant in 4/41 patients (9.7%). The Ki67 index was evaluated in 26/41 (63.4%), and the median positive rate of Ki67 was 20% (range, 7%–93%). The Ki67 index was >30% in 10/26 patients (38.4%). SOX11 was evaluated in 20/41 (48.7%), all of whom (100%) were positive for SOX11. Advanced clinical stage was seen in 36/41 (88%), and the MIPI groupings at diagnosis were as follows: low 11/41 (26.8%), intermediate 16/41 (39%), and high 14/41 (34.1%). The median observation period was 1,637 days (range, 113–4,992 days). ASCT was performed in 13/41 (31%), following R-hyper-CVAD/MA (rituximab, cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate and cytarabine) or CHASER (cyclophosphamide, cytarabine, dexamethasone, etoposide, and rituximab). Patients without upfront ASCT were treated as follows: R-CHOP 16/41 (39%), BR 10/41 (24.3%), R-hyper-CVAD/MA 1/41 (2.4%), and FCR (fludarabine, cyclophosphamide, and rituximab) 1/41 (2.4%). Patient characteristics differed only in terms of age between patients with and without upfront ASCT. The overall response rate was 93% (ASCT 100%; R-CHOP 87.5%; BR 100%). In the whole cohort, 3-year OS and PFS were 72.1% (95%CI: 55.2–83.5%) and 51.1% (95%CI: 34.3–65.6%), respectively. The results of univariate and multivariate analyses for PFS and OS are shown in Table 1. Univariate analysis identified statistically significant differences in age, LDH, and sIL-2R for PFS; and in WBC, LDH, and sIL-2R for OS. Multivariate analyses revealed that age ≥70 years was an independent significant adverse factor for PFS (hazard ratio (HR) 3.23, 95%CI 1.32–7.87; P = 0.009). The cumulative incidence of POD24 at 2 years was 27.3%, and 3-year OS was 36.4% (95%CI: 11.2–62.7) in patients with POD24. In patients without POD24, 3-year OS was 91.8% (95%CI: 70.9–97.9%), which was significantly longer than in patients with POD24 (P < 0.001). There was no significant difference by comparison of initial treatment regimen between the POD24 and non-POD24 groups (P = 0.64). The results of univariate and multivariate analyses for POD24 are shown in Table 2. Univariate analysis identified statistically significant differences in age, LDH, sIL-2R, and blastoid variant for POD24. Multivariate analyses revealed that blastoid variant was an independent significant adverse factor for POD24 (HR 7.21, 95%CI 1.39–37.32; P = 0.018). Salvage treatments were comprised of BR (n = 18), ibrutinib (n = 11), and others. Six patients received BR as retreatment, and the median number of BR retreatments was 2.5 cycles (range, 2–3 cycles). The overall response rates for first BR salvage and BR retreatment were 93.8% and 100%, respectively. In patients with BR retreatment, there was no statistically significant difference in terms of duration of response after second BR (372.5 days [95%CI: 150–NA]) or after first BR (820 days ([95%CI: 295–NA]) (P = 0.09). The following adverse events (grade 3–4) occurred after retreatment of BR: lymphopenia 5/6 (83.3%), neutropenia 1/6 (16%), and CMV infection 2/6 (33%). The duration of ibrutinib treatment was 351 days (range, 30–1,927 days), with four patients in second line, and seven patients in third or later line. In eight patients (excluding three patients with ibrutinib as maintenance following prior chemotherapy), the overall response rate was 50%, and the duration of response to ibrutinib (243.5 days [95%CI: 30–NA]) showed no significant difference compared to that of prior treatment (248 days [95%CI: 90–679]) (P = 0.71). As of the last observation, six patients were continuing ibrutinib and five patients had discontinued ibrutinib due to disease progression (n = 3) or infection (n = 2).
Table 1. Univariate and multivariate analyses of overall survival and progression-free survival.
| Number of patients (n) | Overall survival | Progression-free survival | |||||
|---|---|---|---|---|---|---|---|
| Univariate P value |
Multivariate | Univariate P value |
Multivariate | ||||
| Hazard ratio (95%CI) | P value | Hazard ratio (95%CI) | P value | ||||
| Age | |||||||
| <70 years | 19 | 0.32 | - | - | 0.001 | reference | 0.009 |
| ≥70 years | 22 | - | 3.23 (1.32–7.87) | ||||
| Sex | |||||||
| Male | 31 | 0.70 | - | - | 0.63 | - | - |
| Female | 10 | - | - | ||||
| PS | |||||||
| 0–1 | 38 | 0.13 | - | - | 0.53 | - | - |
| 2–4 | 3 | - | - | ||||
| Clinical stage | |||||||
| Limited | 5 | 0.88 | - | - | 0.57 | - | - |
| Advanced | 36 | - | - | ||||
| WBC | |||||||
| <9,000 U/mL | 33 | 0.015 | reference | 0.074 | 0.61 | - | - |
| ≥9,000 U/mL | 8 | 2.88 (0.90–9.25) | - | ||||
| LDH | |||||||
| <220 U/L | 26 | 0.018 | reference | 0.90 | <0.001 | reference | 0.35 |
| ≥220 U/L | 15 | 0.91 (0.22–3.69) | 1.88 (0.48–7.26) | ||||
| sIL-2R | |||||||
| <1,700 U/mL | 20 | 0.008 | reference | 0.11 | 0.003 | reference | 0.34 |
| ≥1,700 U/mL | 21 | 3.03 (0.77–11.93) | 1.91 (0.50–7.27) | ||||
| Blastoid variant | |||||||
| Non-blastoid variant | 37 | 0.16 | - | - | 0.56 | - | - |
| Blastoid variant | 4 | - | - | ||||
| Ki67 index | |||||||
| <30% | 16 | 0.26 | - | - | 0.12 | - | - |
| ≥30% | 10 | - | - | ||||
PS, performance status; WBC, white blood counts; LDH, lactate dehydrogenase; sIL2-R, soluble interleukin-2 receptor; 95%CI, 95% confidence interval.
Table 2. Univariate and multivariate analyses of progression of disease within 24 months.
| Cumulative incidence of progression of disease within 24 months | |||
|---|---|---|---|
| Univariate P value |
Multivariate | ||
| Hazard ratio (95%CI) | P value | ||
| Age | |||
| <70 years | 0.032 | reference | 0.15 |
| ≥70 years | 3.72 (0.63–21.93) | ||
| Sex | |||
| Male | 0.51 | - | - |
| Female | - | ||
| PS | |||
| 0–1 | 0.11 | - | - |
| 2–4 | - | ||
| Clinical stage | |||
| Limited | 0.67 | - | - |
| Advanced | - | ||
| WBC | |||
| <9,000 U/mL | 0.35 | - | - |
| ≥9,000 U/mL | - | ||
| LDH | |||
| <220 U/L | <0.001 | reference | 0.39 |
| ≥220 U/L | 2.41 (0.31–18.25) | ||
| sIL-2R | |||
| <1,700 U/mL | 0.002 | reference | 0.25 |
| ≥1,700 U/mL | 4.52 (0.34–59.81) | ||
| Blastoid variant | |||
| Non-blastoid variant | 0.01 | reference | 0.018 |
| Blastoid variant | 7.21 (1.39–37.32) | ||
| Ki67 index | |||
| <30% | 0.57 | - | - |
| ≥30% | - | ||
PS, performance status; WBC, white blood counts; LDH, lactate dehydrogenase; sIL2-R, soluble interleukin-2 receptor; 95%CI, 95% confidence interval.
In our study, age was an independent prognostic factor for PFS but not OS, which may be influenced by longer PFS in patients with ASCT and longer survival after progression by effective salvage therapy. However, infection was a serious problem in BR retreatment. There were some serious limitations of our study, including the small sample size which included patients with heterogeneous treatments, as well as the retrospective nature of the study. In the present analysis, blastoid variant was not a poor prognostic factor for OS and PFS, but a predictor of POD24. This result may be due to the small sample size of the study, in addition to the inclusion of one patient with blastoid variant in long-term remission after ASCT. In past reports, blastoid variant has been reported as a poor prognostic factor for MCL, along with high Ki67 index and TP53 mutation.3 In addition, the Ki67 index was not evaluated in almost half of all patients and TP53 mutation was not evaluated in all patients, which are also serious limitations of our study. In conclusion, treatment outcomes of MCL in real-world practice may suggest effective salvage therapy resulted in improvement of prognosis.
Footnotes
FUNDING
This work did not receive any grants from funding agencies in the public, commercial, or not-for-profit sectors.
CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.
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