Early progression of disease predicts shorter survival in MALT lymphoma patients receiving systemic treatment.

Early progression of disease (POD) within two years from diagnosis is linked with poor overall survival (OS) in follicular lymphoma but its prognostic role is less clear in extranodal marginal zone B-cell lymphoma (EMZL). We sought to identify prognostic factors associated with early POD and to determine whether is associated with inferior OS. We analyzed the impact of early POD in the IELSG19 clinical trial dataset (training set of 401 patients randomly assigned to chlorambucil or rituximab or chlorambucil plus rituximab). Reproducibility was examined in a validation set of 287 patients who received systemic treatment. In both sets, we excluded from the analysis the patients who, within 24 months from treatment start, died without progression or were lost to follow-up without prior progression. OS was calculated from progression in patients with early POD and from 24 months after start of treatment in those without (reference group). Early POD was observed in 69 of the 384 (18%) evaluable patients of the IELSG19 study. Patients with high-risk MALT-IPI were more likely to have early POD (p=0.006). The 10-year OS rate was 64% in the early POD group and 85% in the reference group (HR= 2.42, 95%CI, 1.35-4.34; log-rank P=0.002). This prognostic impact was confirmed in the validation set, in which early POD was observed in 64 out of 224 (29%) evaluable patients with 10-year OS rate of 48% in the early POD group and 71% in the reference group (HR= 2.15, 95%CI, 1.19-3.90; log-rank P=0.009). In patients with EMZL who received front-line systemic treatment, early POD is associated with poorer survival and may represent a useful endpoint in future prospective clinical trials.

RCT Entities:   Population Interventions Outcomes

Introduction

Marginal zone lymphomas (MZL) comprise three separate disease entities, which have individual epidemiological, molecular and clinical features. Extranodal marginal zone lymphoma (EMZL), also known as mucosa-associated lymphoid tissue (MALT) lymphoma, is the most common 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 indolent, 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-lymphoma International Prognostic Index (MALT-IPI), which is based on age, disease stage and lactate dehydrogenase (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 factor 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 chlorambucil alone to rituximab alone and to the combination of rituximab 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 treatment, 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 performed in both the test and validation sets, commencing the observation for the group with early POD from the time progression 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 software package (StataCorpLP, College Station, TX, USA). The median follow-up was computed as the median time to censoring or death using the reverse Kaplan-Meier method.[10] Survival probabilities were calculated using life tables and survival curves were estimated 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-

ed for proportions. The c[2] test or Fisher exact test was used as appropriate for comparing proportions. Hazard ratios (HR) and their 95% confidence intervals (95% CI) were estimated using a Cox proportional hazard model. Multivariable analysis of clinical prognostic factors (including the international prognostic scores, IPI[12] and MALT-IPI[7]) for OS was performed by Cox regression[13] with backward stepwise selection. To identify factors associated with early POD, logistic regression was also performed with backwards stepwise selection. P-values <0.05 (two-sided test) were considered statistically significant.

Results

Test set

The analyzed population consisted of 401 patients enrolled in the IELSG-19 study, 131 treated with chlorambucil, 132 with chlorambucil and rituximab and 138 with rituximab; their main clinical features are summarized in Table 1. Estimated hazard curves showed that the peak risk of progression occurred within the first 24 months after diagnosis (Figure 1A). Among these 401 patients, 69 (17%) had early POD, relapsing within 24 months of starting treatment. Of the remaining 332 patients, 315 (79%) had no relapse or death during the first 24 months and form the reference group. Relapses were observed later in 64 (20%) patients in the reference group. Nine patients were lost to follow-up and eight patients died without POD within 24 months of starting treatment (Figure 2, left panel).

Table 1.

The characteristics of the patients in the validation and test sets.

Figure 1.

Risk of disease progression. (A, B) Estimated hazard of progression for patients in the test set, formed of a cohort of individuals from the International Extranodal Lymphoma Study Group-19 (IELSG-19) study (A) and for the patients included in the validation set (B).

Figure 2.

Patients’ distribution. The selection and distribution of patients according to timing of disease progression in the test and validation sets. POD: progression of disease.

The median age of the 69 patients with early POD was 62 years (range: 31 to 81 years), 32 (46%) patients were male and 26 patients (38%) had a primary gastric localization (Table 2).

Table 2.

The distribution of patients’ characteristics in the test and validation sets according to whether they had early progression of disease or not.

Early POD was most frequent in patients with Eastern Cooperative Oncology Group performance status >1 (P=0.042) and elevated serum LDH (P=0.002). Patients with early POD were more likely to have high-risk MALTIPI scores (P=0.005) and high-risk IPI scores (P=0.013) than the reference group. In contrast, elevated serum β[2]- microglobulin level, advanced disease stage (III-IV vs. I-II), multiple extranodal sites of involvement, primary site of disease localization (gastric vs. extra-gastric), age at diagnosis (with either 60 or 70 years cut-off) were not associated with early POD. An unbalanced distribution of patients with early POD was evident across the treatment arms, with early POD occurring more frequently (34/132, 26%) in the single agent rituximab arm and less frequently in the combination treatment arm (13/125, 10%) when compared with the standard arm of single agent chlorambucil (22/127, 17%) (c[2] test, P=0.006) (Table 2).

In a stepwise logistic regression (including the abovementioned individual factors predicting early POD at univariate analysis: treatment arm, LDH concentration, performance status, high-risk IPI score, high-risk MALT-IPI score), only high-risk MALT-IPI score retained statistical significance (P=0.006; odds ratio: 2.39; 95% CI: 1.29-4.45).

The proportion of subjects with early POD was also higher among patients achieving partial remission after first-line therapy than among complete responders (P<0.0001) and, notably, transformation into aggressive histology was detected more frequently in patients with early POD than in the reference group (7/69 vs. 3/315; P<0.0001).

With a median follow-up time of 7.4 years, 18 of 69 patients with early POD died and the OS rates at 5 and 10 years after the risk-defining event were 80% (95% CI: 69-88%) and 64% (95% CI: 45-78%), respectively, in the early POD group versus 91% (95% CI: 87-94%) and 85% (95% CI: 79-90%), respectively, in the reference group (HR=2.42; 95% CI: 1.35-4.35; log-rank P=0.002) (Figure 3A).

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 frontline systemic therapy (B). POD: progression of disease.

Early POD maintained its predictive power with regards to OS (after a risk-defining event) together with a high-risk MALT-IPI score and age (as a continuous variable) in a stepwise Cox model after controlling for treatment arm, LDH concentration, performance status, disease stage, age, Bsymptoms, multiple extranodal sites and high-risk IPI groups (Table 3).

Table 3.

Multivariate analysis for overall survival in the test set (stepwise Cox model, 383 patients).

Validation set

Table 1 shows the main characteristics of the patients in the validation cohort, which comprised 287 MALT lymphoma patients who received front-line systemic treatment (chemotherapy, immunotherapy or both). The median age of this set of patients was 63 years (range: 23 to 92 years). Most of these patients were female (60%).

Estimated hazard curves showed a peak risk of progression at approximately 24 months after diagnosis (Figure 1B). After a median follow-up of 5.7 years, 64 patients (22%) had early POD. Fifty-four patients had a follow-up shorter than 2 years and nine died without prior disease progression within 2 years of starting treatment (Figure 2, right panel). Hence, the reference cohort comprised 160 patients, among whom relapses were later observed in 51 (33%). The early POD rates were similar in the groups of patients receiving different initial therapy (chemotherapy alone, rituximab alone or rituximab combined with different chemotherapeutic or immunomodulatory agents). Similar to the testing cohort, the early POD group was enriched in cases with transformation to aggressive histology (6 of 64 vs. 3 of 160 patients in the reference group, P=0.018) and early POD was most frequent in patients with elevated LDH (P<0.001), high-risk MALT-IPI scores (P=0.001) and high-risk IPI scores (P=0.001) (Table 2). In addition, in the validation cohort, early POD was associated with advanced disease stage (P=0.004) (Table 2).

As in the IELSG-19 study cohort, the patients in the validation set who experienced early POD after systemic therapy had an increased risk of death (HR=2.15; 95% CI: 1.19-3.90; log-rank P=0.009). In the early-POD group, the 5-year OS rate was 70% (95% CI: 54-81%), and the 10- year OS rate was 48% (95% CI: 28-66%). In comparison, the 5-year OS rate in the reference group was 88% (95% CI: 80-93%), and the 10-year OS rate was 71% (95% CI: 58-81%) (Figure 3B).

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 follicular 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 lymphomas, 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 including only EMZL also showed similar PFS rates.[20] We therefore 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 suggested by the abovementioned study from the University of Miami.[20] An observational study of non-follicular indolent 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 thorough description of the clinical features of the EMZL patients with early POD and they did not include independent validation of their findings. Compared to these studies, the present study has additional strengths. It analyzed 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 uniformly 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 heterogeneous series of EMZL cases.[7] which included patients treated with a variety of conventional chemotherapy regimens and immunomodulatory agents in combination with rituximab or not. We showed that our results might be applied to both gastric and extra-gastric primary lymphomas, and to patients receiving different initial therapies.

Histological transformation of MZL is a well-recognized risk factor, which affects the clinical course of the disease. [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 endpoint in future prospective clinical trials.