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Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study
original article
Annals of Oncology 22: 664–670, 2011 doi:10.1093/annonc/mdq418 Published online 19 August 2010
Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study M. Rieger1*, A. O¨sterborg2, R. Pettengell3, D. White4, D. Gill5, J. Walewski6, E. Kuhnt7, M. Loeffler8, M. Pfreundschuh9 & A. D. Ho1, for the MabThera International Trial (MInT) Group 1
Received 23 June 2010; accepted 25 June 2010
original article
Background: The aim of this subgroup analysis of the Mabthera International Trial Group study was to evaluate the impact of chemotherapy and rituximab in primary mediastinal B-cell lymphoma (PMBCL) in comparison to other diffuse large B-cell lymphoma (DLBCL). Methods: Patients were randomly assigned to six cycles of CHOP-like regimens with or without rituximab. Results: Of 824 patients enrolled, 87 had PMBCL and 627 other types of DLBCL. Rituximab increased the rates of complete remission (unconfirmed) in both PMBCL (from 54% to 80%, P = 0.015) and DLBCL (from 72% to 87%, P < 0.001). In PMBCL, rituximab virtually eliminated progressive disease (PD) (2.5% versus 24%, P < 0.001), whereas without rituximab, PD was more frequent in PMBCL than in DLBCL (24% versus 10%, P = 0.010). With a median observation time of 34 months, 3-year event-free survival (EFS) was improved by rituximab for PMBCL (78% versus 52%, P = 0.012) and for DLBCL (81% versus 61%, P < 0.001). Overall survival benefit was similar for DLBCL (93% versus 85%, P < 0.001) and PMBCL (89% versus 78%, P = 0.158). Conclusion: In young patients with PMBCL (age-adjusted International Prognostic Index 0–1), rituximab added to six cycles of CHOP-like chemotherapy increases response rate and EFS to the same extent as other DLBCL. The combination of rituximab with CHOP chemotherapy is an effective treatment in PMBCL with good prognosis features. Key words: MInT, primary mediastinal B-cell lymphoma, rituximab
introduction Primary mediastinal large B-cell lymphoma (PMBCL) was first described in the 1980s [1] and is considered as a distinct entity of diffuse large B-cell lymphoma (DLBCL) representing 2%–4% of non-Hodgkin’s lymphomas [2]. In contrast to the more elderly population affected by DLBCL, PMBCL occurs typically in young adults presenting in their third to forth decade of life with a female predominance [3]. The tumor is usually bulky and up to 50% of the patients have signs and symptoms of superior vena cava syndrome. Systemic involvement at diagnosis is rare and most cases are stages I–II. PMBCL tumors show a variable degree of sclerosis, which can explain the frequent persistence of residual masses even after successful treatment. Interestingly, there are clinicopathologic *Correspondence to: Dr M. Rieger, Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Tel: +49-6221-56 8001; Fax: +49-6221-56 4920; E-mail: [email protected]
similarities between PMBCL and nodular sclerosis subtype of classical Hodgkin’s lymphoma (NScHL). Both entities affect young adults and show the typical localized mediastinal tumor. Moreover, gene expression profiling demonstrated that the molecular signature of PMBCL shares features with NScHL and differs from that of other DLBCL [4, 5]. In the absence of prospective studies, the optimal treatment of PMBCL is still a matter of debate. Uncertainties exist with regard to the intensity of primary chemotherapy, the role of consolidating involved-field radiotherapy (IFRT), and, most importantly, the impact of an additional treatment with rituximab. In comparison with other DLBCL, PMBCL is characterized by a relatively high proportion of patients with primary disease refractoriness or early relapse after standard CHOP-like induction chemotherapy [6–9] and poor response to salvage treatment [10–14]. On the other hand, late relapses after successful first-line therapy are only rarely observed. Because of these characteristics, high efficacy of primary therapy is of key importance for treatment success in PMBCL.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 2Departments of Oncology, Haematology, Karolinska University Hospital, Stockholm, Sweden; 3St George’s University of London, UK; 4Dalhousie University, Halifax, Nova Scotia for the NCIC Clinical Trials Group, Kingston, Ontario, Canada; 5 Department of Haematology, Princess Alexandra Hospital, Queensland, Australia; 6Department of Lymphoma, Maria Sklodowska-Curie Institute and Oncology Centre, Warszawa, Poland; 7Clinical Trial Centre Leipzig, University of Leipzig, Leipzig; 8Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig; 9Saarland University Medical School, Homburg, Germany
original article
Annals of Oncology
patients and methods Patients, diagnostic measures and treatment Patients and details on treatment within the MInT study have been published previously [21]. In brief, eligible were patients aged 18–60 years with untreated aggressive B-cell lymphoma who had no or one risk factor according to age-adjusted International Prognostic Index (aaIPI) in stages II–IV disease or stage I disease with bulky disease. Patients were randomly assigned to six cycles of CHOP-like (CHOP-21, CHOEP-21, MACOP-B and PMitCEBO) chemotherapy and rituximab or to six cycles of CHOPlike chemotherapy alone. IFRT (30–40 Gy, according to national standards) was given to sites of primary bulky disease; radiotherapy (30–40 Gy) to sites of primary extranodal disease was given at the physician’s discretion. According to local guidelines and clinical practice in the respective countries, following different definitions in size of bulky disease (minimal diameter of bulky disease mass) was used in the MInT trial: BNLI (British Lymphoma Group) 5.0 cm; Spanish Hospital’s Group and Polish Lymphoma Group 7 cm; Danish Lymphoma Group and Swedish Lymphoma Group 10 cm and all other participating groups 7.5 cm. Histological diagnosis was reviewed by an experienced national hemopathologist in every participating country and was available for 99% of patients. The study was done in accordance with the Helsinki declaration. The protocol was approved by the ethics review committee of every participating center, and all patients gave written informed consent. The trial is registered at ClinicalTrials.gov, number NCT 00064116. The role of the funding source has been described previously [21].
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end points and assessment of response The primary end point was EFS; secondary end points were complete remission (CR) or unconfirmed complete remission (CRu), progression disease (PD) and OS. EFS was defined as time-to-progressive disease under therapy, the events for which were progressive disease; no achievement of CR or CRu; partial remission; no change; relapse after achievement of CR or CRu or death from any cause, whichever come first. Response was defined as the proportion of patients with CR or CRu after study treatment of all patients assessable for response. Progression under therapy was defined as the proportion of patients with PD during treatment and within 3 months after the end of treatment of all patients assessable for response. OS was defined as time to death from any cause. Patients without an event in EFS or OS were censored at the last day of having valid information for that end point. Response was assessed according to the International Workshop criteria [22] by the treating physician on day 155 after starting treatment.
statistical analysis The methods of the primary analysis of this trial have been published previously [21]. EFS and OS were measured from the date of randomization, estimated according to Kaplan–Meier method and compared by log-rank test. Hazard ratios (HRs) were estimated by Cox regression models to investigate independent risk factors for EFS and OS. Categorical data were presented as absolute and relative frequencies and compared by chi-square test or Fisher’s exact test, as appropriate. Odds ratios were estimated by logistic regression models. Continuous data were reported as mean 6 standard deviation or median and interquartile range and were tested by t-test for independent groups or Mann–Whitney U test, as suitable. In these exploratory analyses, the level of significance was set to 0.05. Statistical analyses were done with SAS 9.1.3.
results A total of 824 patients were enrolled in the prospective and randomized MInT study. Patients with missing informed consent form (n = 1) and patients with other kind of lymphoma than DLBCL (n = 109) were excluded from the current analysis, leaving 714 patients assessable for this analysis. Eight-seven patients were identified with PMBCL and 44 (51%) of them were allocated to receive chemotherapy and rituximab. The remaining 627 patients had DLBCL and 315 (50%) were randomized to receive chemotherapy and rituximab. Patients with PMBCL were younger than those with DLBCL, showed more frequently an elevated lactate dehydrogenase, stage I/II disease, bulky disease, an aaIPI score of 1 and a female predominance (Table 1).
treatment and response According to national standards, different CHOP-like regimes (CHOP-21, CHOEP-21, MACOP-B and PMitCEBO) were used in the trial. The vast majority of patients with PMBCL (92%) and DLBCL (92%) were treated with CHOP-21/CHOEP-21 with or without rituximab. In PMBCL 51% and in DLBCL 50% of the patients were allocated to receive rituximab (chemoimmunotherapy). The different regimens were similarly distributed between the both groups (PMBCL and DLBCL) and are listed in Table 2. In PMBCL after chemo(immuno)therapy, 31 patients (72%) in the CHOP-like-only arm and 37 patients (84%) treated with rituximab achieved CR or PR, respectively. No patient in the
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Therefore, efforts to improve the outcome of PMBCL have focused on strategies of primary chemotherapy dose intensification and radiotherapy consolidation. Several retrospective studies in PMBCL suggested superiority of thirdgeneration regimens, such as MACOP-B, followed by IFRT over CHOP chemotherapy with or without IFRT in terms of response, progression-free survival and overall survival (OS) [11, 12, 15–18]. An alternative approach for improving response rates and outcome of PMBCL might be the addition of CD20 monoclonal antibody rituximab, which has been shown to substantially increase disease control and survival in a variety of B-cell neoplasms (such as DLBCL, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia). However, information on the effect of rituximab in PMBCL is sparse. There are two reports in abstract form, suggesting that chemotherapy in combination with rituximab is associated with a better OS and progression-free survival in comparison with regimens without rituximab [19, 20]. The Mabthera International Trial Group (MInT) trial assessed the role of rituximab in combination with CHOP-like regimens in young patients with good prognosis DLBCL in a prospective randomized phase-III setting. After a median follow-up of 34 months, patients treated with CHOP-like chemotherapy in combination with rituximab had a significant increased 3-year event-free survival (EFS; 79% versus 59%) and OS (93% versus 84%) compared with those assigned to chemotherapy alone [21]. The goal of the present subgroup analysis of the MInT trial was to evaluate the impact of rituximab on the outcome of patients with PMBCL in comparison to other DLBCL.
original article
Annals of Oncology
Table 1. Clinical characteristics of 627 patients with DLBCL and 87 patients with PMBCL PMBCL patients (%)
DLBCL patients (%)
n Age (years) Median (IQR) Range Sex Male Female Bulky disease B symptoms Yes Extranodal sites >1 LDH > UNV >2 fold UNV ECOG performance status >1 Ann Arbor stage I/II BM involvement IPI 0 1
87
627
P valuea
<0.001 36 (27–43) 19–59
46 (38–55) 18–60 <0.001
36 (41) 51 (59) 74 (85)
384 (61) 243 (39) 284 (45)
<0.001
27 (31)
154 (25)
0.172
3 (3.4)
58 (9.3)
0.070
55 (63) 14 (16)
163 (26) 23 (3.7)
<0.001 <0.001
3 (3.4)
3 (0.5)
0.027
80 (92) 2 (2.3)
449 (72) 36 (5.7)
<0.001 0.303 <0.001
22 (25) 65 (75)
286 (46) 341 (54)
a
Mann–Whitney U test, chi-square test or Fisher’s exact test. BM, bone marrow; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; IQR, interquartile range; LDH, lactate dehydrogenase; PMBCL, primary mediastinal B-cell lymphoma; UNV, upper normal value.
Table 2. Distribution of the different treatment regimens CHOP patients (%)
CHOEP patients (%)
MACOP-B patients (%)
PMitCEBO patients (%)
PMBCL All (n = 87) 41 Without 19 rituximab With 22 rituximab DLBCL All (n = 316 627) Without 158 rituximab With 158 rituximab
(47.1) (21.8)
39 (44.8) 20 (23.0)
6 (6.9) 3 (3.4)
1 (1.1) 1 (1.1)
(25.3)
19 (21.8)
3 (3.4)
0
(50.4)
261 (41.6)
27 (4.3)
23 (3.7)
(25.2)
128 (20.4)
13 (2.1)
13 (2.1)
(25.2)
133 (21.2)
14 (2.2)
10 (1.6)
DLBCL, diffuse large B-cell lymphoma; PMBCL, primary mediastinal B-cell lymphoma.
rituximab arm and seven patients in the CHOP-like chemotherapy-only arm had PD. PD was observed after six cycles of chemotherapy in four patients and in three patients after 2, 3 and 4 cycles, respectively (Table 3).
666 | Rieger et al.
PMBCL CHOP-like n = 43 Remission status after chemo(immuno)therapy CR/CRu 14 (32.6%) PR 17 (39.5%) NC 2 (4.7%) PD 7 (16.3%) Death 0 Unknown 3 (7.0%) RT intended 39 (90.7%) RT intended and given 29 (67.4%) RT intended and not given 10 (23.3%) RT not intended 4 (9.3%) RT not intended and given 0 RT not intended and not given 4 (9.3%)
CHOP-like + rituximab n = 44 23 14 4 0 1 2 37 31 6 6 1 6
(52.3%) (31.8%) (9.1%) (2.3%) (4.5%) (84.1%) (70.5%) (13.6%) (13.6%) (2.3%) (13.6%)
CR/CRu, complete response/complete response unconfirmed; NC, no change; PD, progressive disease; PMBCL, primary mediastinal B-cell lymphoma; PR, partial remission; RT, radiotherapy.
In a total of 76 (87%) patients with PMBCL, radiotherapy was intended because of bulky disease or extranodal involvement. In PMBCL, there were 39 patients (51%) treated without rituximab and 37 (49%) with rituximab, respectively, who were designated for radiotherapy. Ten patients without rituximab treatment (one patient in PR, six patients with PD and three with unknown remission status) and six patients (two in CR, two in PR, one with NC and the patient who died) in the rituximab arm were not irradiated despite fulfilling the criteria for being eligible for radiotherapy (Table 3). There was one patient with CR in the rituximab arm who received radiotherapy though not being eligible according to the protocol. Altogether, 18 of 61 irradiated patients (30%) with PMBCL achieved an improvement in response by radiotherapy. Only four patients (7%) had PD following radiotherapy. After chemo(immuno)therapy with or without irradiation, 52 of 77 patients with PMBCL (68%) and 442 of 557 patients with DLBCL (79%) achieved CR/CRu. When treated with rituximab, significantly more patients achieved CR/CRu than without rituximab (PMBCL 80% versus 54%, P = 0.015; DLBCL 87% versus 72%, P < 0.001). Without rituximab, significantly more patients with DLBCL achieved a CR/CRu than those with PMBCL (72% versus 54%, P = 0.029), while the difference between PMBCL and DLBCL regarding the CR/CRu rate was no longer significant when rituximab was given (80% versus 87%, P = 0.24). Treatment with rituximab resulted in a significant reduction of the frequency of PD in PMBCL (2.5% versus 24%, P = 0.006) and in DLBCL (4% versus 10%, P = 0.006), respectively. PD was more frequent in PMBCL than in DLBCL when rituximab was not given (24% versus 10%, P = 0.0095), whereas under treatment with rituximab no difference in PD rate between PMBCL and DLBCL (2.5% versus 3.9%, P = 0.66) was
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Characteristics
Table 3. Response after chemo(immuno)therapy and before intended radiotherapy
original article
Annals of Oncology
observed. The response after study treatment is listed in Table 4.
EFS and OS After a median follow-up of 34 months, there were no differences of EFS {3-year rates: 65% [95% confidence interval (CI) 53% to 75%] versus 71% (95% CI 67% to 75%); log-rank test, P = 0.14} and OS [3-year rates: 83% (95% CI 72% to 90%) versus 89% (95% CI 86% to 91%); log-rank test, P = 0.27] between all patients with PMBCL and all patients with DLBCL, respectively (Figure 1). Of note, only three patients with PMBCL relapsed after achieving CR(u). Two of them within 1 Table 4. Response after treatment comparing PMBCL with DLBCL (assessable cases)
PMBCL CR/CRu PR NC PD Death DLBCL CR/CRu PR NC PD Death
P valuea
Chemotherapy alone Patients (%) [95% CI]
Chemotherapy and rituximab Patients (%) [95% CI]
All
n = 37 20 (54.1) [38.0–70.1] 7 (18.9) [6.3–31.5] 1 (2.7) [0.0–7.9] 9 (24.3) [10.5–38.2] 0 (0.0) n = 275 197 (71.6%) [66.3–77.0] 36 (13.1%) [9.1–17.1] 14 (5.1%) [2.5–7.7] 27 (9.8%) [6.3–13.3] 1 (0.4%)
n = 40 32 (80.0%) [67.6–92.4] 4 (10.0%) [0.7–19.3] 2 (5.0%) [0.0–11.8] 1 (2.5%) [0.0–7.3] 1 (2.5%) n = 282 245 (86.9%) [82.9–90.8] 15 (5.3%) [2.7–7.9] 7 (2.5%) [0.7–4.3] 11 (3.9%) [1.6–6.2] 4 (1.4%)
n = 77 52 (67.5%) [57.1–78.0] 11 (14.3%) [6.5–22.1] 3 (3.9%) [0.0–8.2] 10 (13.0%) [5.5–20.5] 1 (1.3%) n = 557 442 (79.3%) [76.0–82.7] 51 (9.2%) [6.8–11.6] 21 (3.8%) [2.2–5.4] 38 (6.8%) [4.7–8.9] 5 (0.9%)
Patients (%) [95% CI] 0.015
multivariate analyses In multivariate Cox regression (for survival) and logistic regression (for response) analyses restricted to patients treated with CHOP-21 or CHOEP-21 (n = 657), treatment with rituximab and absence of bulky disease remained predictors for a favorable outcome regarding response, EFS and OS. Moreover, the presence of one risk factor according to aaIPI was associated with a lower CR/CRu rate and an inferior EFS. In contrast, histology (PMBCL versus DLBCL) had no impact on response, EFS and OS, and no interaction of rituximab and histology was observed for the several end points (Table 5).
0.006
<0.001
0.006
discussion Due to the absence of prospective randomized PBMCL-specific studies, information on clinical characteristics and treatment outcome in comparison with DLBCL is essentially based on retrospective studies. Preliminary findings suggest that patients with PMBCL are younger (median age 36 versus 46 years) than those with DLBCL, that there is a female predominance and that the majority of the patients with PMBCL have stage I/II
a
Chi-square test or Fisher’s exact test, as appropriate CR/CRu, complete response/complete response unconfirmed; DLBCL, diffuse large B-cell lymphoma; NC, no change; PMBCL, primary mediastinal B-cell lymphoma; PD, progression disease; PR, partial remission.
Overall survival (%)
Event-free survival (%)
100 80 60 40 20
log-rank p = 0.140
0 Numbers at risk: PMBCL other DLBCL
100 80 60 40 20
log-rank p = 0.272
0 0
12
24
36
48
60
0
12
24
36
48
60
87 627
50 428
43 367
27 196
2 54
0 1
87 627
75 554
60 466
33 259
4 79
0 3
Figure 1. Survival of all patients with PMBCL and with DLBCL.
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year after randomization (one treated with rituximab and the other without rituximab). The third patient, who was treated with chemotherapy alone, relapsed 42 months after randomization. Regarding EFS, survival analysis clearly indicates the superiority of additional treatment with rituximab in PMBCL [3-year EFS: 78% (95% CI 61% to 88%) versus 52% (95% CI 35% to 66%); log-rank test, P = 0.012; HR 0.3 (95% CI 0.1–0.8), P = 0.009] and in DLBCL [3-year EFS: 81% (95% CI 76% to 85%) versus 61% (95% CI 55% to 67%); log-rank test, P < 0.0001; HR 0.4 (95% CI 0.3–0.6, P < 0.001)]. EFS was not significantly different comparing PMBCL and DLBCL treated without [3-year EFS: 52% versus 61%; log-rank test, P = 0.13; HR 0.9 (95% CI 0.5–1.5, P = 0.718)] or with rituximab [3-year EFS: 78% versus 81%; log-rank test, P = 0.55; HR 0.9 (95% CI 0.4–1.8), P = 0.740]. Patients with DLBCL showed a better OS when treated with rituximab than without rituximab [3-year OS: 93% (95% CI 89% to 96%) versus 85% (95% CI 80% to 89%); log-rank test P = 0.0005; HR 0.4 (95% CI 0.2--0.7), P < 0.001], whereas the estimated 3-year OS in PMBCL was in the same size and statistically not significant [3-year OS: 88.5% (95% CI 71% to 96%) versus 78.2% (95% CI 61% to 88%); log-rank test, P = 0.16; HR 0.5 (95% CI 0.1–1.6), P = 0.219] (Figure 2).
original article
Annals of Oncology
80 60 40 PMBCL vs other DLBCL R-PMBCL vs R-other DLBCL PMBCL vs R-PMBCL other DLBCL vs R-other DLBCL
20 0
p=0.131 p=0.553 p=0.012 p<0.001
O v e r a l l s u r v iv a l ( % )
E v e n t-f re e s u r v iv a l ( % )
100
100 80 60 40
PMBCL vs other DLBCL R-PMBCL vs R-other DLBCL PMBCL vs R-PMBCL other DLBCL vs R-other DLBCL
20 0
p=0.366 p=0.463 p=0.158 p=0.001
0
12
24
36
48
60
0
12
24
36
48
60
PMBCL other DLBCL
43 312
19 189
17 157
10 80
2 23
0 1
43 312
36 271
27 220
12 119
3 37
0 1
R-PMBCL R- other DLBCL
44 315
31 239
26 210
17 116
0 31
0 0
44 315
39 283
33 246
21 140
1 42
0 2
Numbers at risk:
Figure 2. EFS, and OS of PMBCL and DLBCL assigned to CHOP-like regimens alone or CHOP-like regimens in combination with rituximab.
Covariate Rituximab aaIPI (1) Chemotherapy (CHOEP21 versus CHOP21) Bulky disease Histology (DLBCL versus PMBCL) Interaction histology and rituximab
EFS HR (95% CI)
P value
OS HR (95% CI)
P value
CR(u) OR (95% CI)
0.33 (0.14–0.77) 1.77 (1.28–2.45) 0.80 (0.59–1.08)
0.010 0.001 0.150
0.33 (0.09–1.24) 1.33 (0.81–2.17) 1.11 (0.70–1.76)
0.101 0.258 0.652
3.70 (1.25–10.96) 0.50 (0.32–0.78) 1.62 (1.05–2.50)
0.018 0.003 0.028
0.09 (0.01–0.75) 2.13 (1.00–4.54) 1.16 (0.61–2.22)
0.026 0.050 0.653
1.48 (1.08–2.04) 0.89 (0.53–1.50)
0.015 0.665
2.27 (1.36–3.79) 0.98 (0.45–2.14)
0.002 0.964
0.44 (0.28–0.70) 1.47 (0.68–3.19)
<0.001 0.325
4.86 (2.05–11.50) 0.63 (0.25–1.58)
<0.001 0.327
1.18 (0.48–2.90)
0.725
1.14 (0.27–4.80)
0.855
0.87 (0.26–2.84)
0.812
2.77 (0.28–27.48)
0.385
P value
PD OR (95% CI)
P value
aaIPI, age-adjusted International Prognostic Index; CI, confidence interval; CRu, complete remission or unconfirmed complete remission; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; HR, hazard ratio; OR, odds ratio; OS, overall survival; PD, progressive disease; PMBCL, primary mediastinal B-cell lymphoma.
disease with bulky mediastinal mass [11, 23–27]. The present subgroup analysis of the MInT trial largely confirms these findings. In terms of clinical management, experience with CHOP-like chemotherapy indicated that PMBCL has a more aggressive clinical course than DLBCL with a substantial percentage of patients with primary refractory disease or early relapse [28, 29]. Moreover, patients with PMBCL who failed primary treatment seemed to have a substantially worse prognosis than those with DLBCL relapse due to poor efficacy of salvage regimens including high-dose chemotherapy and autologous stem cell transplantation in PMBCL [13, 17, 30]. The results of this analysis of the MInT study show for the first time prospectively that the CR rate after CHOP-like chemotherapy without rituximab in PMBCL is indeed substantially lower than for DLBCL (54% versus 72%), whereas, conversely, the PD rate in PMBCL is substantially higher than in DLBCL (24% versus 10%). Interestingly, in most cases (seven of nine), PD occurred while still on chemotherapy before a planned radiotherapy could be conducted. Since relapses were virtually absent in PMBCL, but not in DLBCL once CR/CRu was achieved, 3-year EFS of patients with PMBCL, however, was not significantly inferior to that of patients with DLBCL even if rituximab had not been added to
668 | Rieger et al.
primary chemotherapy. The finding that relapses in PMBCL beyond 2 years after initial therapy seem to be a rare event is in accordance with previous reports [17, 30–32]. Since PMBCL was highly (but not entirely) correlated with bulky disease and bulky disease has been shown to be a significant outcome predictor (with much stronger impact in the no-rituximab group than in the rituximab group) in a previous analysis of the MInT trial [33], one might speculate that the inferior response rate of PMBCL compared with DLBCL in the absence of rituximab treatment is due to bulky disease rather than to genuine biological characteristics of the disease itself. Accordingly, bulky disease, but not disease histology, remained as independent EFS and OS predictors in our Cox models. However, the PMBCL-typical treatment failure pattern (high proportion of primary PD but virtual absence of relapse from CR) suggests that the biological peculiarities of PMBCL are not fully explained by excess bulky disease in this entity. On the other hand, rituximab virtually eliminated primary PD in both PMBCL and DLBCL, thereby increasing CR rates, overall response and EFS significantly for both subsets. This benefit translated into an OS advantage to a similar extent in both entities (DLBCL 93% versus 85% and PMBCL 89% versus 78%), which was, however, not significant in PMBCL due to
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Table 5. Multivariate analysis for EFS, OS, CR(u) and PD
original article
Annals of Oncology
conclusions The present study shows for the first time in a prospective fashion that rituximab significantly increases response rate and 3-year EFS in PMBCL. This benefit is largely due to virtual elimination of primary PD by rituximab. With rituximab, overall response rate and 3-year EFS of PMBCL are similar to that of DLBCL. Whereas the inferior response rates of PMBCL in comparison to DLBCL in the absence of rituximab seem to be related to bulky disease rather than to histology, the typical treatment failure pattern of PMBCL nevertheless suggests fundamental biological differences to other DLBCL. The combination of rituximab with CHOP chemotherapy is an effective treatment at least in PMBCL with good prognosis features.
funding Roche (Basel, Switzerland) (M 39045).
acknowledgement Contribution: MP was the principal investigator of the MInT study. EK, ML and MR did the statistical analysis. MP, AO, RP, DW, DG, JW and ADH are involved in conception and design and provided patients. MR and ADH were responsible for writing this report and the other authors contributed to the discussion of the report. All authors gave final approval of manuscript.
disclosure RP has honoraria (Roche) to disclose. DW is member of the Roche advisory board and received honoraria. JW has
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honoraria, research funding, expert testimony and other remuneration from Roche to disclose. MP is member of the Roche advisory board and has research funding to disclose. All other authors have declared no conflicts of interest.
references 1. Lichtenstein AK, Levine A, Taylor CR et al. Primary mediastinal lymphoma in adults. Am J Med 1980; 68: 509–514. 2. Gaulard P, Harris NL, Pileri SA et al. Primary mediastinal (thymic) large B-cell lymphoma. In Swerdlow SH, Campo E, Harris NL (eds), et al. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC Press 2008; 250–251. 3. Boleti E, Johnson PW. Primary mediastinal B-cell lymphoma. Hematol Oncol 2007; 25: 157–163. 4. Savage KJ, Monti S, Kutok JL et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 2003; 102: 3871–3879. 5. Rosenwald A, Wright G, Leroy K et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 2003; 198: 851–862. 6. Todeschini G, Ambrosetti A, Meneghini V et al. Mediastinal large-B-cell lymphoma with sclerosis: a clinical study of 21 patients. J Clin Oncol 1990; 8: 804–808. 7. Kirn D, Mauch P, Shaffer K et al. Large-cell and immunoblastic lymphoma of the mediastinum: prognostic features and treatment outcome in 57 patients. J Clin Oncol 1993; 11: 1336–1343. 8. Hamlin PA, Portlock CS, Straus DJ et al. Primary mediastinal large B-cell lymphoma: optimal therapy and prognostic factor analysis in 141 consecutive patients treated at Memorial Sloan Kettering from 1980 to 1999. Br J Haematol 2005; 130: 691–699. 9. Haioun C, Gaulard P, Roudot-Thoraval F et al. Mediastinal diffuse large-cell lymphoma with sclerosis: a condition with a poor prognosis. Am J Clin Oncol 1989; 12: 425–429. 10. Sehn LH, Antin JH, Shulman LN et al. Primary diffuse large B-cell lymphoma of the mediastinum: outcome following high-dose chemotherapy and autologous hematopoietic cell transplantation. Blood 1998; 91: 717–723. 11. Todeschini G, Secchi S, Morra E et al. Primary mediastinal large B-cell lymphoma (PMLBCL): long-term results from a retrospective multicentre Italian experience in 138 patients treated with CHOP or MACOP-B/VACOP-B. Br J Cancer 2004; 90: 372–376. 12. Zinzani PL, Martelli M, Bendandi M et al. Primary mediastinal large B-cell lymphoma with sclerosis: a clinical study of 89 patients treated with MACOP-B chemotherapy and radiation therapy. Haematologica 2001; 86: 187–191. 13. Kuruvilla J, Pintilie M, Tsang R et al. Salvage chemotherapy and autologous stem cell transplantation are inferior for relapsed or refractory primary mediastinal large B-cell lymphoma compared with diffuse large B-cell lymphoma. Leuk Lymphoma 2008; 49: 1329–1336. 14. De Sanctis V, Finolezzi E, Osti MF et al. MACOP-B and involved-field radiotherapy is an effective and safe therapy for primary mediastinal large B cell lymphoma. Int J Radiat Oncol Biol Phys 2008; 72: 1154–1160. 15. Zinzani PL, Martelli M, Magagnoli M et al. Treatment and Clinical Management of Primary Mediastinal Large B-Cell Lymphoma With Sclerosis: MACOP-B Regimen and Mediastinal Radiotherapy Monitored by 67Gallium Scan in 50 Patients. Blood 1999; 94: 3289–3293. 16. Zinzani PL, Martelli M, Bertini M et al. Induction chemotherapy strategies for primary mediastinal large B-cell lymphoma with sclerosis: a retrospective multinational study on 426 previously untreated patients. Haematologica 2002; 87: 1258–1264. 17. Savage KJ, Al-Rajhi N, Voss N et al. Favorable outcome of primary mediastinal large B-cell lymphoma in a single institution: the British Columbia experience. Ann Oncol 2006; 17: 123–130. 18. Martelli MP, Martelli M, Pescarmona E et al. MACOP-B and involved field radiation therapy is an effective therapy for primary mediastinal large B-cell lymphoma with sclerosis. Ann Oncol 1998; 9: 1027–1029.
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the smaller number of patients. No interaction of study treatment and histology was revealed for any end point, again suggesting that rituximab is similarly effective in both entities. Our observation that in PMBCL a benefit in survival occurs when rituximab was added to CHOP-like regimens is in line with two smaller retrospective studies published in abstract form. Dunleavy et al. [19] reported that the addition from rituximab to DA-EPOCH-chemotherapy significantly improved EFS and OS in PMBCL. Avigdor et al. demonstrated an improved PFS in PMBCL caused by addition of rituximab to VACOP-B or CHOP chemotherapy. Furthermore, a superior PFS with VACOP-B compared with CHOP was observed, but this advantage in favor of the more intensive regimen (VACOP-B) was lost after the introduction of rituximab [20]. In contrast, a recently published retrospective study in PMBCL showed no significant differences in terms of CR rate and relapse-free survival after treatment with MACOP-B/VACOP-B with or without an additional treatment with rituximab [34]. The value of consolidating IFRT in PMBCL is still matter of debate [14, 27]. Our observation that in PMBCL, radiotherapy was able to improve the remission status in 30% of patients irradiated might point to a possible benefit of this strategy; however, it cannot be excluded that this increase of response rates is due to the natural disappearance of masses not containing malignant cells after chemo(immuno)therapy only.
original article
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27. Mazzarotto R, Boso C, Vianello F et al. Primary mediastinal large B-cell lymphoma: results of intensive chemotherapy regimens (MACOP-B/VACOP-2B) plus involved field radiotherapy on 53 patients. A single institution experience. Int J Radiat Oncol Biol Phys. 2007; 68: 823–829. 28. Lavabre-Bertrand T, Donadio D, Fegueux N et al. A study of 15 cases of primary mediastinal lymphoma of B-cell type. Cancer 1992; 69: 2561–2566. 29. Perrone T, Frizzera G, Rosai J. Mediastinal diffuse large-cell lymphoma with sclerosis. A clinicopathologic study of 60 cases. Am J Surg Pathol 1986; 10: 176–191. 30. Massoud M, Koscielny S, Lapusan S et al. Primary mediastinal large B-cell lymphomas treated with dose-intensified CHOP alone or CHOP combined with radiotherapy. Leuk Lymphoma 2008; 49: 1510–1515. 31. Kolonic SO, Dzebro S, Kusec R et al. Primary mediastinal large B-cell lymphoma: a single-center study of clinicopathologic characteristics. Int J Hematol 2006; 83: 331–336. 32. Vassilakopoulos TP, Angelopoulou MK, Galani Z et al. Rituximab-CHOP (R-CHOP) and radiotherapy (RT) for primary mediastinal large B-cell lymphoma (PMLBCL). Blood 2006; 108(11). (Abstr 2745). 33. Pfreundschuh M, Tru¨mper L, Osterborg A et al. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study. Lancet Oncol 2008; 9: 435–444. 34. Zinzani PL, Stefoni V, Finolezzi E et al. Rituximab combined with MACOP-B or VACOP-B and radiation therapy in primary mediastinal large Bcell lymphoma: a retrospective study. Clin Lymphoma Myeloma 2009; 9: 381–385.
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19. Dunleavy K, Pittaluga S, Janik J et al. Primary mediastinal large B-cell lymphoma (PMBL) outcome may be significantly improved by the addition of rituximab to dose-adjusted (DA)-EPOCH and cbviates the need for radiation: results from a prospective study of 44 patients. Blood 2006; 108(11). (Abstr 209). 20. Avigdor A, Sirotkin T, Shemtov N et al. Combination of rituximab with initial chemotherapy improves outcome of primary mediastinal B-cell lymphoma: a retrospective analysis of a single institution cohort. Blood 2007; 110(11). (Abstr 1283). 21. Pfreundschuh M, Tru¨mper L, Osterborg A et al. CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with goodprognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group. Lancet Oncol 2006; 7: 379–391. 22. Cheson BD, Horning SJ, Coiffier B et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol 1999; 17: 1244. 23. Cazals-Hatem D, Lepage E, Brice P et al. A clinicopathologic study of 141 cases compared with 916 nonmediastinal large B-cell lymphomas, a GELA (‘‘Groupe d’Etude des Lymphomes de l’Adulte’’) study. Am J Surg Pathol 1996; 20: 877–888. 24. Besien K van, Kelta M, Bahaguna P. Primary mediastinal B-cell lymphoma: a review of pathology and management. J Clin Oncol 2001; 19: 1855–1864. 25. Lazzarino M, Orlandi E, Paulli M et al. Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: a multicenter study of 106 patients. J Clin Oncol 1997; 15: 1646–1653. 26. Nguyen LN, Ha CS, Hess M et al. The outcome of combined-modality treatments for stage I and II primary large B-cell lymphoma of the mediastinum. Int J Radiat Oncol Biol Phys. 2000; 47: 1281–1285.
Annals of Oncology
Annals of Oncology 22: 664–670, 2011 doi:10.1093/annonc/mdq418 Published online 19 August 2010
Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: results of the Mabthera International Trial Group study M. Rieger1*, A. O¨sterborg2, R. Pettengell3, D. White4, D. Gill5, J. Walewski6, E. Kuhnt7, M. Loeffler8, M. Pfreundschuh9 & A. D. Ho1, for the MabThera International Trial (MInT) Group 1
Received 23 June 2010; accepted 25 June 2010
original article
Background: The aim of this subgroup analysis of the Mabthera International Trial Group study was to evaluate the impact of chemotherapy and rituximab in primary mediastinal B-cell lymphoma (PMBCL) in comparison to other diffuse large B-cell lymphoma (DLBCL). Methods: Patients were randomly assigned to six cycles of CHOP-like regimens with or without rituximab. Results: Of 824 patients enrolled, 87 had PMBCL and 627 other types of DLBCL. Rituximab increased the rates of complete remission (unconfirmed) in both PMBCL (from 54% to 80%, P = 0.015) and DLBCL (from 72% to 87%, P < 0.001). In PMBCL, rituximab virtually eliminated progressive disease (PD) (2.5% versus 24%, P < 0.001), whereas without rituximab, PD was more frequent in PMBCL than in DLBCL (24% versus 10%, P = 0.010). With a median observation time of 34 months, 3-year event-free survival (EFS) was improved by rituximab for PMBCL (78% versus 52%, P = 0.012) and for DLBCL (81% versus 61%, P < 0.001). Overall survival benefit was similar for DLBCL (93% versus 85%, P < 0.001) and PMBCL (89% versus 78%, P = 0.158). Conclusion: In young patients with PMBCL (age-adjusted International Prognostic Index 0–1), rituximab added to six cycles of CHOP-like chemotherapy increases response rate and EFS to the same extent as other DLBCL. The combination of rituximab with CHOP chemotherapy is an effective treatment in PMBCL with good prognosis features. Key words: MInT, primary mediastinal B-cell lymphoma, rituximab
introduction Primary mediastinal large B-cell lymphoma (PMBCL) was first described in the 1980s [1] and is considered as a distinct entity of diffuse large B-cell lymphoma (DLBCL) representing 2%–4% of non-Hodgkin’s lymphomas [2]. In contrast to the more elderly population affected by DLBCL, PMBCL occurs typically in young adults presenting in their third to forth decade of life with a female predominance [3]. The tumor is usually bulky and up to 50% of the patients have signs and symptoms of superior vena cava syndrome. Systemic involvement at diagnosis is rare and most cases are stages I–II. PMBCL tumors show a variable degree of sclerosis, which can explain the frequent persistence of residual masses even after successful treatment. Interestingly, there are clinicopathologic *Correspondence to: Dr M. Rieger, Department of Internal Medicine V, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany. Tel: +49-6221-56 8001; Fax: +49-6221-56 4920; E-mail: [email protected]
similarities between PMBCL and nodular sclerosis subtype of classical Hodgkin’s lymphoma (NScHL). Both entities affect young adults and show the typical localized mediastinal tumor. Moreover, gene expression profiling demonstrated that the molecular signature of PMBCL shares features with NScHL and differs from that of other DLBCL [4, 5]. In the absence of prospective studies, the optimal treatment of PMBCL is still a matter of debate. Uncertainties exist with regard to the intensity of primary chemotherapy, the role of consolidating involved-field radiotherapy (IFRT), and, most importantly, the impact of an additional treatment with rituximab. In comparison with other DLBCL, PMBCL is characterized by a relatively high proportion of patients with primary disease refractoriness or early relapse after standard CHOP-like induction chemotherapy [6–9] and poor response to salvage treatment [10–14]. On the other hand, late relapses after successful first-line therapy are only rarely observed. Because of these characteristics, high efficacy of primary therapy is of key importance for treatment success in PMBCL.
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; 2Departments of Oncology, Haematology, Karolinska University Hospital, Stockholm, Sweden; 3St George’s University of London, UK; 4Dalhousie University, Halifax, Nova Scotia for the NCIC Clinical Trials Group, Kingston, Ontario, Canada; 5 Department of Haematology, Princess Alexandra Hospital, Queensland, Australia; 6Department of Lymphoma, Maria Sklodowska-Curie Institute and Oncology Centre, Warszawa, Poland; 7Clinical Trial Centre Leipzig, University of Leipzig, Leipzig; 8Institute of Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig; 9Saarland University Medical School, Homburg, Germany
original article
Annals of Oncology
patients and methods Patients, diagnostic measures and treatment Patients and details on treatment within the MInT study have been published previously [21]. In brief, eligible were patients aged 18–60 years with untreated aggressive B-cell lymphoma who had no or one risk factor according to age-adjusted International Prognostic Index (aaIPI) in stages II–IV disease or stage I disease with bulky disease. Patients were randomly assigned to six cycles of CHOP-like (CHOP-21, CHOEP-21, MACOP-B and PMitCEBO) chemotherapy and rituximab or to six cycles of CHOPlike chemotherapy alone. IFRT (30–40 Gy, according to national standards) was given to sites of primary bulky disease; radiotherapy (30–40 Gy) to sites of primary extranodal disease was given at the physician’s discretion. According to local guidelines and clinical practice in the respective countries, following different definitions in size of bulky disease (minimal diameter of bulky disease mass) was used in the MInT trial: BNLI (British Lymphoma Group) 5.0 cm; Spanish Hospital’s Group and Polish Lymphoma Group 7 cm; Danish Lymphoma Group and Swedish Lymphoma Group 10 cm and all other participating groups 7.5 cm. Histological diagnosis was reviewed by an experienced national hemopathologist in every participating country and was available for 99% of patients. The study was done in accordance with the Helsinki declaration. The protocol was approved by the ethics review committee of every participating center, and all patients gave written informed consent. The trial is registered at ClinicalTrials.gov, number NCT 00064116. The role of the funding source has been described previously [21].
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end points and assessment of response The primary end point was EFS; secondary end points were complete remission (CR) or unconfirmed complete remission (CRu), progression disease (PD) and OS. EFS was defined as time-to-progressive disease under therapy, the events for which were progressive disease; no achievement of CR or CRu; partial remission; no change; relapse after achievement of CR or CRu or death from any cause, whichever come first. Response was defined as the proportion of patients with CR or CRu after study treatment of all patients assessable for response. Progression under therapy was defined as the proportion of patients with PD during treatment and within 3 months after the end of treatment of all patients assessable for response. OS was defined as time to death from any cause. Patients without an event in EFS or OS were censored at the last day of having valid information for that end point. Response was assessed according to the International Workshop criteria [22] by the treating physician on day 155 after starting treatment.
statistical analysis The methods of the primary analysis of this trial have been published previously [21]. EFS and OS were measured from the date of randomization, estimated according to Kaplan–Meier method and compared by log-rank test. Hazard ratios (HRs) were estimated by Cox regression models to investigate independent risk factors for EFS and OS. Categorical data were presented as absolute and relative frequencies and compared by chi-square test or Fisher’s exact test, as appropriate. Odds ratios were estimated by logistic regression models. Continuous data were reported as mean 6 standard deviation or median and interquartile range and were tested by t-test for independent groups or Mann–Whitney U test, as suitable. In these exploratory analyses, the level of significance was set to 0.05. Statistical analyses were done with SAS 9.1.3.
results A total of 824 patients were enrolled in the prospective and randomized MInT study. Patients with missing informed consent form (n = 1) and patients with other kind of lymphoma than DLBCL (n = 109) were excluded from the current analysis, leaving 714 patients assessable for this analysis. Eight-seven patients were identified with PMBCL and 44 (51%) of them were allocated to receive chemotherapy and rituximab. The remaining 627 patients had DLBCL and 315 (50%) were randomized to receive chemotherapy and rituximab. Patients with PMBCL were younger than those with DLBCL, showed more frequently an elevated lactate dehydrogenase, stage I/II disease, bulky disease, an aaIPI score of 1 and a female predominance (Table 1).
treatment and response According to national standards, different CHOP-like regimes (CHOP-21, CHOEP-21, MACOP-B and PMitCEBO) were used in the trial. The vast majority of patients with PMBCL (92%) and DLBCL (92%) were treated with CHOP-21/CHOEP-21 with or without rituximab. In PMBCL 51% and in DLBCL 50% of the patients were allocated to receive rituximab (chemoimmunotherapy). The different regimens were similarly distributed between the both groups (PMBCL and DLBCL) and are listed in Table 2. In PMBCL after chemo(immuno)therapy, 31 patients (72%) in the CHOP-like-only arm and 37 patients (84%) treated with rituximab achieved CR or PR, respectively. No patient in the
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Therefore, efforts to improve the outcome of PMBCL have focused on strategies of primary chemotherapy dose intensification and radiotherapy consolidation. Several retrospective studies in PMBCL suggested superiority of thirdgeneration regimens, such as MACOP-B, followed by IFRT over CHOP chemotherapy with or without IFRT in terms of response, progression-free survival and overall survival (OS) [11, 12, 15–18]. An alternative approach for improving response rates and outcome of PMBCL might be the addition of CD20 monoclonal antibody rituximab, which has been shown to substantially increase disease control and survival in a variety of B-cell neoplasms (such as DLBCL, follicular lymphoma, mantle cell lymphoma and chronic lymphocytic leukemia). However, information on the effect of rituximab in PMBCL is sparse. There are two reports in abstract form, suggesting that chemotherapy in combination with rituximab is associated with a better OS and progression-free survival in comparison with regimens without rituximab [19, 20]. The Mabthera International Trial Group (MInT) trial assessed the role of rituximab in combination with CHOP-like regimens in young patients with good prognosis DLBCL in a prospective randomized phase-III setting. After a median follow-up of 34 months, patients treated with CHOP-like chemotherapy in combination with rituximab had a significant increased 3-year event-free survival (EFS; 79% versus 59%) and OS (93% versus 84%) compared with those assigned to chemotherapy alone [21]. The goal of the present subgroup analysis of the MInT trial was to evaluate the impact of rituximab on the outcome of patients with PMBCL in comparison to other DLBCL.
original article
Annals of Oncology
Table 1. Clinical characteristics of 627 patients with DLBCL and 87 patients with PMBCL PMBCL patients (%)
DLBCL patients (%)
n Age (years) Median (IQR) Range Sex Male Female Bulky disease B symptoms Yes Extranodal sites >1 LDH > UNV >2 fold UNV ECOG performance status >1 Ann Arbor stage I/II BM involvement IPI 0 1
87
627
P valuea
<0.001 36 (27–43) 19–59
46 (38–55) 18–60 <0.001
36 (41) 51 (59) 74 (85)
384 (61) 243 (39) 284 (45)
<0.001
27 (31)
154 (25)
0.172
3 (3.4)
58 (9.3)
0.070
55 (63) 14 (16)
163 (26) 23 (3.7)
<0.001 <0.001
3 (3.4)
3 (0.5)
0.027
80 (92) 2 (2.3)
449 (72) 36 (5.7)
<0.001 0.303 <0.001
22 (25) 65 (75)
286 (46) 341 (54)
a
Mann–Whitney U test, chi-square test or Fisher’s exact test. BM, bone marrow; DLBCL, diffuse large B-cell lymphoma; ECOG, Eastern Cooperative Oncology Group; IPI, International Prognostic Index; IQR, interquartile range; LDH, lactate dehydrogenase; PMBCL, primary mediastinal B-cell lymphoma; UNV, upper normal value.
Table 2. Distribution of the different treatment regimens CHOP patients (%)
CHOEP patients (%)
MACOP-B patients (%)
PMitCEBO patients (%)
PMBCL All (n = 87) 41 Without 19 rituximab With 22 rituximab DLBCL All (n = 316 627) Without 158 rituximab With 158 rituximab
(47.1) (21.8)
39 (44.8) 20 (23.0)
6 (6.9) 3 (3.4)
1 (1.1) 1 (1.1)
(25.3)
19 (21.8)
3 (3.4)
0
(50.4)
261 (41.6)
27 (4.3)
23 (3.7)
(25.2)
128 (20.4)
13 (2.1)
13 (2.1)
(25.2)
133 (21.2)
14 (2.2)
10 (1.6)
DLBCL, diffuse large B-cell lymphoma; PMBCL, primary mediastinal B-cell lymphoma.
rituximab arm and seven patients in the CHOP-like chemotherapy-only arm had PD. PD was observed after six cycles of chemotherapy in four patients and in three patients after 2, 3 and 4 cycles, respectively (Table 3).
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PMBCL CHOP-like n = 43 Remission status after chemo(immuno)therapy CR/CRu 14 (32.6%) PR 17 (39.5%) NC 2 (4.7%) PD 7 (16.3%) Death 0 Unknown 3 (7.0%) RT intended 39 (90.7%) RT intended and given 29 (67.4%) RT intended and not given 10 (23.3%) RT not intended 4 (9.3%) RT not intended and given 0 RT not intended and not given 4 (9.3%)
CHOP-like + rituximab n = 44 23 14 4 0 1 2 37 31 6 6 1 6
(52.3%) (31.8%) (9.1%) (2.3%) (4.5%) (84.1%) (70.5%) (13.6%) (13.6%) (2.3%) (13.6%)
CR/CRu, complete response/complete response unconfirmed; NC, no change; PD, progressive disease; PMBCL, primary mediastinal B-cell lymphoma; PR, partial remission; RT, radiotherapy.
In a total of 76 (87%) patients with PMBCL, radiotherapy was intended because of bulky disease or extranodal involvement. In PMBCL, there were 39 patients (51%) treated without rituximab and 37 (49%) with rituximab, respectively, who were designated for radiotherapy. Ten patients without rituximab treatment (one patient in PR, six patients with PD and three with unknown remission status) and six patients (two in CR, two in PR, one with NC and the patient who died) in the rituximab arm were not irradiated despite fulfilling the criteria for being eligible for radiotherapy (Table 3). There was one patient with CR in the rituximab arm who received radiotherapy though not being eligible according to the protocol. Altogether, 18 of 61 irradiated patients (30%) with PMBCL achieved an improvement in response by radiotherapy. Only four patients (7%) had PD following radiotherapy. After chemo(immuno)therapy with or without irradiation, 52 of 77 patients with PMBCL (68%) and 442 of 557 patients with DLBCL (79%) achieved CR/CRu. When treated with rituximab, significantly more patients achieved CR/CRu than without rituximab (PMBCL 80% versus 54%, P = 0.015; DLBCL 87% versus 72%, P < 0.001). Without rituximab, significantly more patients with DLBCL achieved a CR/CRu than those with PMBCL (72% versus 54%, P = 0.029), while the difference between PMBCL and DLBCL regarding the CR/CRu rate was no longer significant when rituximab was given (80% versus 87%, P = 0.24). Treatment with rituximab resulted in a significant reduction of the frequency of PD in PMBCL (2.5% versus 24%, P = 0.006) and in DLBCL (4% versus 10%, P = 0.006), respectively. PD was more frequent in PMBCL than in DLBCL when rituximab was not given (24% versus 10%, P = 0.0095), whereas under treatment with rituximab no difference in PD rate between PMBCL and DLBCL (2.5% versus 3.9%, P = 0.66) was
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Characteristics
Table 3. Response after chemo(immuno)therapy and before intended radiotherapy
original article
Annals of Oncology
observed. The response after study treatment is listed in Table 4.
EFS and OS After a median follow-up of 34 months, there were no differences of EFS {3-year rates: 65% [95% confidence interval (CI) 53% to 75%] versus 71% (95% CI 67% to 75%); log-rank test, P = 0.14} and OS [3-year rates: 83% (95% CI 72% to 90%) versus 89% (95% CI 86% to 91%); log-rank test, P = 0.27] between all patients with PMBCL and all patients with DLBCL, respectively (Figure 1). Of note, only three patients with PMBCL relapsed after achieving CR(u). Two of them within 1 Table 4. Response after treatment comparing PMBCL with DLBCL (assessable cases)
PMBCL CR/CRu PR NC PD Death DLBCL CR/CRu PR NC PD Death
P valuea
Chemotherapy alone Patients (%) [95% CI]
Chemotherapy and rituximab Patients (%) [95% CI]
All
n = 37 20 (54.1) [38.0–70.1] 7 (18.9) [6.3–31.5] 1 (2.7) [0.0–7.9] 9 (24.3) [10.5–38.2] 0 (0.0) n = 275 197 (71.6%) [66.3–77.0] 36 (13.1%) [9.1–17.1] 14 (5.1%) [2.5–7.7] 27 (9.8%) [6.3–13.3] 1 (0.4%)
n = 40 32 (80.0%) [67.6–92.4] 4 (10.0%) [0.7–19.3] 2 (5.0%) [0.0–11.8] 1 (2.5%) [0.0–7.3] 1 (2.5%) n = 282 245 (86.9%) [82.9–90.8] 15 (5.3%) [2.7–7.9] 7 (2.5%) [0.7–4.3] 11 (3.9%) [1.6–6.2] 4 (1.4%)
n = 77 52 (67.5%) [57.1–78.0] 11 (14.3%) [6.5–22.1] 3 (3.9%) [0.0–8.2] 10 (13.0%) [5.5–20.5] 1 (1.3%) n = 557 442 (79.3%) [76.0–82.7] 51 (9.2%) [6.8–11.6] 21 (3.8%) [2.2–5.4] 38 (6.8%) [4.7–8.9] 5 (0.9%)
Patients (%) [95% CI] 0.015
multivariate analyses In multivariate Cox regression (for survival) and logistic regression (for response) analyses restricted to patients treated with CHOP-21 or CHOEP-21 (n = 657), treatment with rituximab and absence of bulky disease remained predictors for a favorable outcome regarding response, EFS and OS. Moreover, the presence of one risk factor according to aaIPI was associated with a lower CR/CRu rate and an inferior EFS. In contrast, histology (PMBCL versus DLBCL) had no impact on response, EFS and OS, and no interaction of rituximab and histology was observed for the several end points (Table 5).
0.006
<0.001
0.006
discussion Due to the absence of prospective randomized PBMCL-specific studies, information on clinical characteristics and treatment outcome in comparison with DLBCL is essentially based on retrospective studies. Preliminary findings suggest that patients with PMBCL are younger (median age 36 versus 46 years) than those with DLBCL, that there is a female predominance and that the majority of the patients with PMBCL have stage I/II
a
Chi-square test or Fisher’s exact test, as appropriate CR/CRu, complete response/complete response unconfirmed; DLBCL, diffuse large B-cell lymphoma; NC, no change; PMBCL, primary mediastinal B-cell lymphoma; PD, progression disease; PR, partial remission.
Overall survival (%)
Event-free survival (%)
100 80 60 40 20
log-rank p = 0.140
0 Numbers at risk: PMBCL other DLBCL
100 80 60 40 20
log-rank p = 0.272
0 0
12
24
36
48
60
0
12
24
36
48
60
87 627
50 428
43 367
27 196
2 54
0 1
87 627
75 554
60 466
33 259
4 79
0 3
Figure 1. Survival of all patients with PMBCL and with DLBCL.
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year after randomization (one treated with rituximab and the other without rituximab). The third patient, who was treated with chemotherapy alone, relapsed 42 months after randomization. Regarding EFS, survival analysis clearly indicates the superiority of additional treatment with rituximab in PMBCL [3-year EFS: 78% (95% CI 61% to 88%) versus 52% (95% CI 35% to 66%); log-rank test, P = 0.012; HR 0.3 (95% CI 0.1–0.8), P = 0.009] and in DLBCL [3-year EFS: 81% (95% CI 76% to 85%) versus 61% (95% CI 55% to 67%); log-rank test, P < 0.0001; HR 0.4 (95% CI 0.3–0.6, P < 0.001)]. EFS was not significantly different comparing PMBCL and DLBCL treated without [3-year EFS: 52% versus 61%; log-rank test, P = 0.13; HR 0.9 (95% CI 0.5–1.5, P = 0.718)] or with rituximab [3-year EFS: 78% versus 81%; log-rank test, P = 0.55; HR 0.9 (95% CI 0.4–1.8), P = 0.740]. Patients with DLBCL showed a better OS when treated with rituximab than without rituximab [3-year OS: 93% (95% CI 89% to 96%) versus 85% (95% CI 80% to 89%); log-rank test P = 0.0005; HR 0.4 (95% CI 0.2--0.7), P < 0.001], whereas the estimated 3-year OS in PMBCL was in the same size and statistically not significant [3-year OS: 88.5% (95% CI 71% to 96%) versus 78.2% (95% CI 61% to 88%); log-rank test, P = 0.16; HR 0.5 (95% CI 0.1–1.6), P = 0.219] (Figure 2).
original article
Annals of Oncology
80 60 40 PMBCL vs other DLBCL R-PMBCL vs R-other DLBCL PMBCL vs R-PMBCL other DLBCL vs R-other DLBCL
20 0
p=0.131 p=0.553 p=0.012 p<0.001
O v e r a l l s u r v iv a l ( % )
E v e n t-f re e s u r v iv a l ( % )
100
100 80 60 40
PMBCL vs other DLBCL R-PMBCL vs R-other DLBCL PMBCL vs R-PMBCL other DLBCL vs R-other DLBCL
20 0
p=0.366 p=0.463 p=0.158 p=0.001
0
12
24
36
48
60
0
12
24
36
48
60
PMBCL other DLBCL
43 312
19 189
17 157
10 80
2 23
0 1
43 312
36 271
27 220
12 119
3 37
0 1
R-PMBCL R- other DLBCL
44 315
31 239
26 210
17 116
0 31
0 0
44 315
39 283
33 246
21 140
1 42
0 2
Numbers at risk:
Figure 2. EFS, and OS of PMBCL and DLBCL assigned to CHOP-like regimens alone or CHOP-like regimens in combination with rituximab.
Covariate Rituximab aaIPI (1) Chemotherapy (CHOEP21 versus CHOP21) Bulky disease Histology (DLBCL versus PMBCL) Interaction histology and rituximab
EFS HR (95% CI)
P value
OS HR (95% CI)
P value
CR(u) OR (95% CI)
0.33 (0.14–0.77) 1.77 (1.28–2.45) 0.80 (0.59–1.08)
0.010 0.001 0.150
0.33 (0.09–1.24) 1.33 (0.81–2.17) 1.11 (0.70–1.76)
0.101 0.258 0.652
3.70 (1.25–10.96) 0.50 (0.32–0.78) 1.62 (1.05–2.50)
0.018 0.003 0.028
0.09 (0.01–0.75) 2.13 (1.00–4.54) 1.16 (0.61–2.22)
0.026 0.050 0.653
1.48 (1.08–2.04) 0.89 (0.53–1.50)
0.015 0.665
2.27 (1.36–3.79) 0.98 (0.45–2.14)
0.002 0.964
0.44 (0.28–0.70) 1.47 (0.68–3.19)
<0.001 0.325
4.86 (2.05–11.50) 0.63 (0.25–1.58)
<0.001 0.327
1.18 (0.48–2.90)
0.725
1.14 (0.27–4.80)
0.855
0.87 (0.26–2.84)
0.812
2.77 (0.28–27.48)
0.385
P value
PD OR (95% CI)
P value
aaIPI, age-adjusted International Prognostic Index; CI, confidence interval; CRu, complete remission or unconfirmed complete remission; DLBCL, diffuse large B-cell lymphoma; EFS, event-free survival; HR, hazard ratio; OR, odds ratio; OS, overall survival; PD, progressive disease; PMBCL, primary mediastinal B-cell lymphoma.
disease with bulky mediastinal mass [11, 23–27]. The present subgroup analysis of the MInT trial largely confirms these findings. In terms of clinical management, experience with CHOP-like chemotherapy indicated that PMBCL has a more aggressive clinical course than DLBCL with a substantial percentage of patients with primary refractory disease or early relapse [28, 29]. Moreover, patients with PMBCL who failed primary treatment seemed to have a substantially worse prognosis than those with DLBCL relapse due to poor efficacy of salvage regimens including high-dose chemotherapy and autologous stem cell transplantation in PMBCL [13, 17, 30]. The results of this analysis of the MInT study show for the first time prospectively that the CR rate after CHOP-like chemotherapy without rituximab in PMBCL is indeed substantially lower than for DLBCL (54% versus 72%), whereas, conversely, the PD rate in PMBCL is substantially higher than in DLBCL (24% versus 10%). Interestingly, in most cases (seven of nine), PD occurred while still on chemotherapy before a planned radiotherapy could be conducted. Since relapses were virtually absent in PMBCL, but not in DLBCL once CR/CRu was achieved, 3-year EFS of patients with PMBCL, however, was not significantly inferior to that of patients with DLBCL even if rituximab had not been added to
668 | Rieger et al.
primary chemotherapy. The finding that relapses in PMBCL beyond 2 years after initial therapy seem to be a rare event is in accordance with previous reports [17, 30–32]. Since PMBCL was highly (but not entirely) correlated with bulky disease and bulky disease has been shown to be a significant outcome predictor (with much stronger impact in the no-rituximab group than in the rituximab group) in a previous analysis of the MInT trial [33], one might speculate that the inferior response rate of PMBCL compared with DLBCL in the absence of rituximab treatment is due to bulky disease rather than to genuine biological characteristics of the disease itself. Accordingly, bulky disease, but not disease histology, remained as independent EFS and OS predictors in our Cox models. However, the PMBCL-typical treatment failure pattern (high proportion of primary PD but virtual absence of relapse from CR) suggests that the biological peculiarities of PMBCL are not fully explained by excess bulky disease in this entity. On the other hand, rituximab virtually eliminated primary PD in both PMBCL and DLBCL, thereby increasing CR rates, overall response and EFS significantly for both subsets. This benefit translated into an OS advantage to a similar extent in both entities (DLBCL 93% versus 85% and PMBCL 89% versus 78%), which was, however, not significant in PMBCL due to
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Table 5. Multivariate analysis for EFS, OS, CR(u) and PD
original article
Annals of Oncology
conclusions The present study shows for the first time in a prospective fashion that rituximab significantly increases response rate and 3-year EFS in PMBCL. This benefit is largely due to virtual elimination of primary PD by rituximab. With rituximab, overall response rate and 3-year EFS of PMBCL are similar to that of DLBCL. Whereas the inferior response rates of PMBCL in comparison to DLBCL in the absence of rituximab seem to be related to bulky disease rather than to histology, the typical treatment failure pattern of PMBCL nevertheless suggests fundamental biological differences to other DLBCL. The combination of rituximab with CHOP chemotherapy is an effective treatment at least in PMBCL with good prognosis features.
funding Roche (Basel, Switzerland) (M 39045).
acknowledgement Contribution: MP was the principal investigator of the MInT study. EK, ML and MR did the statistical analysis. MP, AO, RP, DW, DG, JW and ADH are involved in conception and design and provided patients. MR and ADH were responsible for writing this report and the other authors contributed to the discussion of the report. All authors gave final approval of manuscript.
disclosure RP has honoraria (Roche) to disclose. DW is member of the Roche advisory board and received honoraria. JW has
Volume 22 | No. 3 | March 2011
honoraria, research funding, expert testimony and other remuneration from Roche to disclose. MP is member of the Roche advisory board and has research funding to disclose. All other authors have declared no conflicts of interest.
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the smaller number of patients. No interaction of study treatment and histology was revealed for any end point, again suggesting that rituximab is similarly effective in both entities. Our observation that in PMBCL a benefit in survival occurs when rituximab was added to CHOP-like regimens is in line with two smaller retrospective studies published in abstract form. Dunleavy et al. [19] reported that the addition from rituximab to DA-EPOCH-chemotherapy significantly improved EFS and OS in PMBCL. Avigdor et al. demonstrated an improved PFS in PMBCL caused by addition of rituximab to VACOP-B or CHOP chemotherapy. Furthermore, a superior PFS with VACOP-B compared with CHOP was observed, but this advantage in favor of the more intensive regimen (VACOP-B) was lost after the introduction of rituximab [20]. In contrast, a recently published retrospective study in PMBCL showed no significant differences in terms of CR rate and relapse-free survival after treatment with MACOP-B/VACOP-B with or without an additional treatment with rituximab [34]. The value of consolidating IFRT in PMBCL is still matter of debate [14, 27]. Our observation that in PMBCL, radiotherapy was able to improve the remission status in 30% of patients irradiated might point to a possible benefit of this strategy; however, it cannot be excluded that this increase of response rates is due to the natural disappearance of masses not containing malignant cells after chemo(immuno)therapy only.
original article
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Annals of Oncology