Frontline antibiotic therapy for early‐stage Helicobacter pylori‐negative gastric MALT lymphoma

Abstract

To the Editor: At least two-thirds of gastric mucosa-associated lymphoid tissue (MALT) lymphomas are associated with a chronic Helicobacter pylori (HP) infection, and HP eradication with triple antibiotic therapy is an effective treatment for patients with early-stage disease. Currently, a definitive involved site radiation, at a dose of 24-30 Gy, is the preferred frontline treatment for patients with HP-negative localized disease. Monotherapy with rituximab or chemoimmunotherapy are an alternative for patients in whom radiotherapy is contraindicated, but they are relatively expensive and can be less effective. Successful treatment of HP-negative early stage MALT lymphoma with HP-directed antibiotic therapy has been reported in several small cases series. However, larger studies are needed to confirm whether frontline antibiotics may be an effective treatment for patients with early-stage HP-negative gastric MALT lymphoma and, most importantly, whether its initial use may hamper the efficacy of subsequent treatments. We identified 26 patients with stage IAE HP-negative gastric MALT lymphoma, who received frontline triple antibiotic therapy, consisting of 14 days of amoxicillin or metronidazole, clarithromycin, and a proton-pump inhibitor, at our institution between 01/1991 and 12/2011. A group of 38 HP-positive patients, treated with frontline antibiotic therapy during the same time frame, matched by age, sex, race, and stage, was used as control. Stage was defined according to the Lugano staging system, and included esophagogastroduodenoscopy (EGD) with multiple biopsies and endoscopic ultrasound. HP status was determined by tissue immunohistochemistry (IHC) and serum antibody assay. Response to therapy was assessed by repeated EGD and biopsies at least 2 months after treatment, and complete remission (CR) was defined according to guidelines. No repeated imaging was required to confirm CR. Endoscopic surveillance was performed every 12-18 months. Association with categorical variables was evaluated using χ or Fisher exact tests. Progression-free survival (PFS) and overall survival (OS) were defined as the time from the start of therapy to progression of disease, and/or death, or last follow-up, respectively. PFS and OS were calculated using Kaplan-Meier estimates and compared using the log-rank test. A P value of ≤0.05 (two tailed) was considered statistically significant (SPSS v23). Baseline characteristics are shown in Supporting Information S1. After frontline antibiotic therapy, 6 (23%) HP-negative patients and 18 (47%) HP-positive patients achieved complete response (CR1) (P = 0.07), after a median of 2 months (range, 1-6 months) and 7 months (range, 1-13)(P = 0.009), respectively (Supporting Information S1). Among 16 HP-negative patients with residual disease after frontline antibiotic therapy, 10 received radiotherapy and 6 were placed on surveillance; among 18 HP-positive patients with residual disease after frontline therapy, 5 received radiotherapy and 13 were observed. All 15 patients treated with consolidative radiotherapy achieved CR (CR2). Overall, combining CR1 and CR2, 16 (62%) HP-negative patients and 23 HP-positive patients (61%) achieved CR (P = 1) (Supporting Information S1). All 19 patients not receiving consolidative radiotherapy progressed during surveillance, after a median of 13 months (range, 1-36 months). Among the 10 HP-negative patients who had residual disease and were surveilled, 9 had a local relapse and 1 had an extra-nodal relapse without transformation; a second course of antibiotic therapy was attempted in 3 patients, and 1 achieved CR. Among the 15 HP-positive patients who had residual disease and were surveilled, 13 had a local relapse, and 2 had an extra-nodal relapse without transformation; a second course of antibiotic therapy was attempted in 7 patients, and 3 achieved CR. After a median follow-up of 11 years (95% confidence interval [CI], 9-13 years), 13 (50%) HP-negative patients and 21 (55%) HPpositive patients relapsed and/or progressed, and median PFS was 38 months in both groups (P = 0.78). Among 24 patients who achieved CR1, 6 relapsed: of these 6, 2 were HP-negative and 4 were HP-positive (Figure 1A). Median PFS was not reached for patients achieving CR1 or CR2, whereas it was 6 months for patients not achieving CR (Figure 1B). Among HP-negative patients, salvage therapy included: radiotherapy in 4 patients, antibiotics in 3, chemoradiotherapy in 2, rituximab in 2, chemotherapy alone in 1, and radioimmunotherapy in 1 patient. Among HP-positive patients, salvage therapy included: antibiotics in 7 patients, chemotherapy alone in 5, radiotherapy in 4, chemo-radiotherapy in 1, rituximab in 1, radioimmunotherapy in 1, and gastrectomy in 1 patient. Response to salvage therapy was 69% among HP-negative patients and 60% among HP-positive patients (P = 1) (Supporting Information S1). Among patients who received repeated antibiotic therapy, 1 out of 3 HPnegative patients and 4 out of 7 HP-positive patients achieved CR. Of interest, IHC for HP infection was repeated in all 10 cases, and was unchanged as compared to baseline. At the most recent follow-up, 6 (33%) HP-negative and 9 (34%) HP-positive patients have died. Median OS was 17.5 and 20.4 years, Received: 18 January 2019 Revised: 8 February 2019 Accepted: 19 February 2019