Prospective Phase II trial of radiation therapy in localised non-gastric marginal zone lymphoma with prospective evaluation of autoimmunity and Helicobacter pylori status: TROG 05.02/ALLG NHL15

Highlights

• Largest prospective radiotherapy trial in non-gastric marginal zone lymphoma.

• Conducted to a high standard by a cooperative oncology group with quality assurance.

• Unique prospective autoimmunity data in non-gastric marginal zone lymphoma.

• Prospective evaluation for Helicobacter pylori infection.

• Trial is among the highest-level evidence currently available in this disease.

Abstract

Background

This Phase 2 multicentre trial in localised non-gastric marginal zone lymphoma (MZL) evaluated the effectiveness and safety of radiotherapy and documented markers of autoimmunity and Helicobacter pylori infection.

Patients and methods

Eligible patients had Stages I and II or paired-organ, non-gastric MZL. Bone marrow evaluation, autoantibody panel, and H. pylori evaluation were mandatory. Involved-field or involved-site radiotherapy was delivered to 24–30.6 Gy. Detected H. pylori infections underwent eradication.

Results

Between 2006 and 2014, six centres enrolled 70 patients, and 68 commenced treatment. The median age was 59 (range: 23–84) years, and 31 (46%) were male. Overall, 55 patients had Stage I disease, nine patients had Stage II disease, and four patients had paired organ–confined disease. Involved extranodal sites with three or more cases were orbital (n = 18), conjunctiva (n = 13), lacrimal (n = 8), skin (n = 8), salivary (n = 7), and muscle (n = 4). Eight patients had primary nodal MZL. At the median follow-up of 5 years (range 0.7–9.4), progression-free survival and overall survival were 79% and 95%, respectively. One lymphoma-related death and two in-field failures (after 25 and 30 Gy, respectively) occurred. Distant relapse sites were skin (n = 2), lymph nodes (n = 2), duodenum, stomach, muscle, and conjunctiva (1 each). No paired-organ MZL relapsed. Apart from cataracts (n = 18), only three treatment-related late grade ≥3 adverse events occurred. Autoantibodies or autoimmune events were detected in 26 of 68 patients (38%). H. pylori infection was detected in 15 of 63 patients (24%) tested. Neither autoimmunity nor H. pylori was detected in 27 of 68 patients (40%).

Conclusions

Radiotherapy was a potentially curative treatment with low toxicity in localised non-gastric MZL. Autoimmunity, H. pylori infection or both were detected in 60% of patients.

Introduction

Low-grade marginal zone lymphomas (MZLs) are highly radiosensitive B cell malignancies that commonly present with localised disease and are often immunologically driven [1,2]. The Trans Tasman Radiation Oncology Group (TROG) conducted the first prospective multicentre Phase II clinical trial of radiotherapy (RT) in localised non-gastric MZL, aiming to rigorously define the efficacy and toxicity of RT and to systematically investigate potential causative factors of localised MZL. Localised non-gastric MZLs arise in a diverse range of organs and have different underlying causes and predisposing factors. They share a core set of molecular characteristics with each other and with gastric mucosa-associated lymphoid tissue (MALT) lymphomas [3]. Retrospective studies suggest that RT is an effective curative-intent treatment with low toxicity.

The 2016 World Health Organization classification described extranodal, nodal, and splenic MZLs [4]. Extranodal MZLs arise most commonly from MALT and are described as ‘MALT’ lymphomas. MALT lymphoma can involve bilaterally paired organs (e.g. salivary glands [5], orbital adnexa [6], or breast [7]) and may still be cured by local therapy [8]. Nodal MZLs are less common and arise in lymph nodes without apparent involvement of an extranodal site [9]. Splenic MZLs are dissimilar to MALT and nodal MZLs and are not curable by local therapies, although splenectomy may be beneficial [10].

Gastric MALT lymphomas are usually associated with Helicobacter pylori infection. H. pylori eradication can result in durable disease regression [11], especially in t(11:18) negative cases [12]. RT is usually curative if H. pylori eradication does not induce remission [13,14]. Common non-gastric extranodal MZL sites include salivary glands, lacrimal glands, conjunctivae, lung, thyroid, and bowel [15]. Chronic inflammation associated with autoimmune disease, such as Sjogren's syndrome [16] or Hashimoto's thyroiditis [17], and infective agents, including H. pylori [18] and Chlamydia psittaci [19], have all been associated with non-gastric MZL. No previous prospective study has attempted to systematically characterise predisposing factors for localised non-gastric MZL, document local and distant disease control with RT, and comprehensively report RT toxicity. A previous Austrian study reported a >40% incidence of gastric H. pylori infection in non-gastric MZL of various stages [20], and authors from MD Anderson Cancer Center reported endoscopically detected gastric MALT lymphoma in 4 of 16 patients with non-gastrointestinal MALT lymphomas [21].

In our trial, eligible patients had localised MZL at any non-gastric site (Stage I–II or disease confined to bilaterally paired organs). Patients were tested for active gastric H. pylori infection, and H. pylori–infected patients underwent gastroscopy to exclude concurrent gastric lymphoma. Patients were screened for common autoantibodies, and any clinical evidence of autoimmune disease was recorded. Trial RT doses were informed primarily by retrospective data from Princess Margaret Hospital, Toronto [22].