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Early disease progression in EMZL
Introduction
Marginal zone lymphomas (MZL) comprise three sepa- rate disease entities, which have individual epidemiologi- cal, molecular and clinical features. Extranodal marginal zone lymphoma (EMZL), also known as mucosa-associat- ed lymphoid tissue (MALT) lymphoma, is the most com- mon MZL subtype, accounting for approximately 50 to 70% of MZL and 5% to 8% of all B-cell lymphomas.1-3 EMZL may involve virtually any tissue but most often affects organs that are normally devoid of lymphocytes, where it arises from lymphoid populations associated with chronic inflammatory processes of either infectious or autoimmune origin.4 The clinical presentation is very heterogeneous and EMZL patients are managed with a variety of treatments. The natural course is usually indo- lent, particularly in patients with gastric lymphomas, and aggressive therapy is rarely required.1,3,5 Outcomes may, however, differ depending on the organ involved.2,6 We recently proposed a prognostic model, the MALT-lym- phoma International Prognostic Index (MALT-IPI), which is based on age, disease stage and lactate dehydrogenase
Table 1. The characteristics of the patients in the validation and test sets.
(LDH) concentration at diagnosis. MALT-IPI discriminated between patients with different progression-free survival (PFS) and overall survival (OS), and retained its prognostic utility in both gastric and non-gastric MALT lymphomas.7 In this context, the identification of the minority of patients with shorter survival may become important, especially in the perspective of personalized medicine, and might form the basis for adapting therapeutic approaches.
In follicular lymphoma early progression of disease (POD), namely, within 24 months after diagnosis, has been reported to be associated with poor outcomes.8 Currently, the clinical significance of early POD in EMZL is uncertain, and the impact of early POD on subsequent survival has not been properly explored yet.
The present study aimed to understand whether time to progression after first-line systemic therapy may be a fac- tor affecting survival outcomes in EMZL. We analyzed data from the International Extranodal Lymphoma Study Group 19 (IELSG-19) clinical trial to determine whether early POD is predictive of inferior OS in this disease, and then validated our findings in an independent cohort.
Methods
Patients
Details regarding the IELSG-19 randomized phase III trial (ClinicalTrials.gov Identifier: NCT 00210353) have been published elsewhere.6,9 All patients provided written informed consent and the study was approved by the institutional review board or ethics committee of each institution involved. This trial compared chlo- rambucil alone to rituximab alone and to the combination of rit- uximab and chlorambucil as front-line therapy in EMZL patients, with event-free survival as the primary endpoint.6
Early POD was defined as in the follicular lymphoma study by Casulo et al.8 Patients enrolled in the IELSG-19 study were divided into two groups: a group formed of patients with early POD, that is, progression within 24 months from the start of first-line treat- ment, and a reference group, consisting of patients without early POD. An independent validation set, comprising only patients who received front-line systemic treatment (chemotherapy, immunotherapy or both), was derived from the validation cohort of the MALT-IPI study, which included patients from different sources (the databases of the IELSG-1 multicenter study and of a retrospective survey conducted at the Oncology Institute of Southern Switzerland, and at the Hematology Division of the University of Eastern Piedmont, in Novara Italy, and a cohort of patients diagnosed at the Medical University of Vienna, Austria) whose details have also been published elsewhere.7
Statistical methods
Primary analysis of OS from risk-defining events was per- formed in both the test and validation sets, commencing the observation for the group with early POD from the time progres- sion occurred, and for the reference group from 24 months after the start of front-line therapy.
Statistical analysis was performed using the Stata/SE 11.0 soft- ware package (StataCorpLP, College Station, TX, USA). The medi- an follow-up was computed as the median time to censoring or death using the reverse Kaplan-Meier method.10 Survival probabil- ities were calculated using life tables and survival curves were esti- mated by the method of Kaplan-Meier; differences between groups of patients were evaluated using the log-rank test.11 Binomial exact 95% confidence intervals (95% CI) were calculat-
Number of patients
Test set (IELSG-19)
401
2003-2010
61 years (51-69) 197/204
175 (44%)
6 (1.5%)
42 (10.5%) 46 (16%) 171 (43%) 77 (19%)
68 (17%)
131 (33%) 132 (33%) 0% 138 (34%) 0%
7.4 years (5.6-9.7)
62.8% (57.6-67.6) 50.8% (44.5-56.8) NR (2.6-NR)
90.3% (86.9-92.9) 80.0% (74.3-84.7) NR
Validation set
287
1983-2014
63 years (51-72) 115/172
140 (49%) 14 (5%)
42 (16%)
73 (43%) 125 (44%) 88 (31%)
69 (26%)
158 (55%) 64 (22%) 60 (21%) 28 (10%) 37 (13%)
5.7 years (2.3-9.2)
46.9% (39.8-53.6)
29.7% (21.6-38.2)
4.6 years (1.8-15.1)
85.7% (80.1-89.9)
70.3% (61.3-77.6)
17 years (8.18-NR)
Years of diagnosis
Median age at diagnosis (IQR) Male/female ratio
Stage III-IV, n (%) Performance status>1a, n (%) LDH >UNLb, n (%)
β -microglobulin >UNLC, n (%) 2
Primary gastric lymphoma, n (%)
IPI, high-intermediate/high riskd, n (%) MALT-IPI, high riske, n (%)
First-line treatment, n (%) Chemotherapy only
Rituximab and chemotherapy Doxorubicin-containing regimen Rituximab only
Otherf
Median follow-up (IQR)
Progression-free survival 5-year PFS rate (95% CI) 10-year PFS rate (95% CI) Median (IQR)
Overall survival
5-year OS rate (95% CI) 10-year OS rate (95% CI) Median (IQR)
IELSG-19: International Extranodal Lymphoma Study Group-19 study; IQR: interquartile range; LDH: serum lactate dehydrogenase; UNL: upper normal limit; IPI: International Prognostic Index; MALT-IPI: Mucosa-Associated Lymphoid Tissue lymphoma International Prognostic Index;PFS:progression-free survival,95% CI:95% confidence interval;OS:overall survival; NR: not reached. aEastern Cooperative Oncology Group performance status report- ed in 282 cases in the validation set. bReported in 264 cases in the validation set. cAssessed in only 289 patients in the test set and 168 in the validation set. dDefined in 281 patients in the validation set. eDefined in 267 patients in the validation set. fOther comprises: lenalido- mide in combination with rituximab (15 patients), lenalidomide as a single agent (12 patients), interferon-a (4 patients), bortezomib (3 patients), thalidomide (2 patients), and ofatumomab (1 patient).
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