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A. Conconi et al.
AB
Figure 3. Overall survival. (A, B) Kaplan-Meier estimates of overall survival and their confidence intervals according to the occurrence of early progression of disease in patients enrolled in the International Extranodal Lymphoma Study Group-19 randomized clinical trial (A) and in the validation set of patients who received front- line systemic therapy (B). POD: progression of disease.
Discussion
The present study provides the first validated evidence that early POD, defined as lymphoma progression within 2 years after initial treatment, is a powerful tool to predict long-term survival in EMZL.
Early POD is a widely accepted survival predictor in fol- licular lymphoma,8,14-18 with many studies showing that 20% of patients relapse within 2 years of treatment regardless of the addition of maintenance rituximab.8 In a heterogeneous group of indolent non follicular B-cell lym- phomas, a retrospective study from the Mayo Clinic and University of Iowa found that event-free survival at 12 months was associated with a better outcome.19 However, in keeping with follicular lymphoma, the IELSG-19 study showed a PFS at 2 years of approximately 20%.6 A large retrospective series from the University of Miami includ- ing only EMZL also showed similar PFS rates.20 We there- fore decided to maintain the 24-month time-span, already validated in follicular lymphoma, in our EMZL analysis. Our choice was further justified by the estimated hazard curves showing that the peak risk of progression occurred within 2 years.
A potential prognostic relevance of early POD was sug- gested by the abovementioned study from the University of Miami.20 An observational study of non-follicular indo- lent lymphomas by the Italian Lymphoma Foundation (FIL) also found that early POD has a prognostic value in MZL.21 However, none of these reports provided a thor- ough description of the clinical features of the EMZL patients with early POD and they did not include inde- pendent validation of their findings. Compared to these studies, the present study has additional strengths. It ana- lyzed the impact of early POD in a cohort of patients prospectively collected in the largest controlled clinical trial performed so far in EMZL, with histological diagnosis confirmed by central pathology review and with uniform- ly defined follow-up investigations.
The external validation strengthens our findings. The
prognostic impact of early POD in EMZL was confirmed in an independent cohort, obtained by merging three hetero- geneous series of EMZL cases.7 which included patients treated with a variety of conventional chemotherapy regi- mens and immunomodulatory agents in combination with rituximab or not. We showed that our results might be applied to both gastric and extra-gastric primary lym- phomas, and to patients receiving different initial therapies.
Histological transformation of MZL is a well-recognized risk factor, which affects the clinical course of the dis- ease.22-24 The significant proportion of cases with evidence of transformation to aggressive histologies among patients relapsing early after systemic treatment may contribute to the inferior outcome seen in this study. This observation emphasizes the need for repeated histological evaluations, in particular in the case of early relapse, since cases with transformed histology require more intensive therapy.
In conclusion, we provide novel evidence that, in patients with EMZL who received front-line systemic treatment, early POD is associated with poor survival and should be further investigated as a potentially useful end- point in future prospective clinical trials.
Acknowledgments
The authors thank the IELSG-19 study investigators, data managers, and nursing staff. The authors also thank Ayda Lüönd and Rita Gianascio Gianocca for excellent secretarial assistance.
Funding
This work was partly supported by the International Extranodal Lymphoma Study Group; by a grant from Oncosuisse (ICP OCS-01356-03-2003); AIRC 5 x 1000 (n. 21198), AIRC, Milan, Italy; and the AGING Project, Department of Excellence (DIMET), Universita’ del Piemonte Orientale, Novara, Italy. The IELSG-19 clinical trial was sup- ported in part by an unrestricted research grant from Roche International, Ltd. The funders had no role in study design, data collection, analysis, and interpretation, or writing of the report.
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