Trial Information

Multicentre,Prospective Study of First-Line Antibiotic Therapy for Early-Stage Low-Grade and High-Grade Gastric Mucosa-Associated Lymphoid Tissue-Type Lymphoma and Potential Predicting Factor for Treatment Outcome

Background: Eradication of Helicobacter pylori (Hp) infection is well recognized as the
initial therapy for early-stage low-grade gastric mucosa-associated lymphoid tissue-type
lymphoma (lg-MALT lymphoma). On the other hand, high-grade transformed MALT lymphoma
(hg-MALT lymphoma) is generally considered to arise from Hp-independent clones and thus to
be unlikely to respond to antibiotic therapy. Our previous prospective studies have firstly
demonstrated that 1st-line antibiotic therapy could achieve durable complete histological
remission in two-third of Hp-positive stage IE hg-MALT lymphoma (Chen et al., J. Clin.
Oncol., 2001), in which the long-term clinical outcomes were equivalent to those achievable
in lg-MALT lymphoma (Chen et al. J Natl Cancer Inst, accepted). In addition, our laboratory
studies have confirmed that t(11;18) translocation is associated with loss of Hp-dependence
in lg-MALT lymphoma but infrequently found in high-grade tumors. We also found that nuclear
translocation of NF-kB or BCL-10 (by immunohistochemical, IHC, staining) were useful markers
to predict the Hp-dependence of both early-stage gastric hg- and lg-MALT lymphoma to
antibiotic therapy (Kuo et al. JCO 2004 & Yeh et al. Blood 2005). In addition, recent data
suggested cytochrome CYP2C18/19 genetic polymorphisms are associated with the metabolism of
omeprazole, and thus the genotype of such enzymes might affect the efficacy of antibiotics
for eradication of Hp infection.

Aims: A nationwide study to prospectively validate

1. The complete histological and molecular remission rate for antibiotics as 1st-line
therapy for Hp-positive early-stage gastric lg- and hg-MALT lymphoma

2. The durability of complete histological remission after antibiotics

3. The usefulness of pattern of NF-kB and BCL-10 by IHC staining in prospectively
predicting the Hp-dependence of gastric lg- and hg-MALT lymphoma

4. The frequency of t(11;18) translocation in gastric lg- and hg-MALT lymphoma in Taiwan.

5. The association between the CYP2C18/19 genetic polymorphisms and eradication of Hp
infection after antibiotics.

Materials and Methods: Patients with newly, histologically proven stage IE / IIE-1 gastric
lg- and hg-MALT lymphoma are eligible. Pre-treatment Hp infection status will be determined
by histology, rapid urease test and serology. At time of registration, patients should agree
to provide endoscopic biopsy specimen, including eight 4-mm histologic section for
immunohistochemical study of NF-kB and BCL-10 and three 10-mm of section in eppendorf tube
for RNA extraction and subsequent RT-PCR for t(11;18) translocation determination, which
will be performed at the central laboratory. In addition, serum (from 5 mL of coagulated
blood) as well as peripheral blood mononuclear cells (from 3 mL of heparized blood) will
also collected before treatment for Hp-serology and CYP 2C18/19 genetic polymorphism
detection, respectively. Hp-positive patients will receive 2-week of triple therapy,
consisting of omeprazole, amoxicillin and clarithromycin (OAC regimen), and have first
follow-up endoscopy 4 weeks later to determine the status of Hp infection and tumor
response. Patients will then have sequential follow-up endoscopic examinations every 3
months until complete histological remission (CR) or disease progression; then every 6
months for complete responders. Patients with hg-MALT lymphoma who have stable or
progressive disease after Hp eradication will immediately refer for systemic chemotherapy.
CR was defined as regression of lymphoid infiltration to Wotherspoon’s score <2 on all
pathological sections of endoscopic biopsy specimens. The predictive value of NF-kB, BCL-10
and t(11;18) for complete histological remission after Hp eradication will be determined.

Expected Results: 1st-line antibiotic therapy will achieve complete histologic remission in
70-80% of Hp-positive stage IE gastric lg-MALT lymphoma and in 50-60% of stage IE hg-MALT
lymphoma. The objective histologic CR rate in stage IIE-1 disease may be 30-40% for
low-grade tumor and 20-30% for high-grade ones. The sensitivity and specificity of NF-kB and
BCL-10 positive nuclear staining by IHC and of t(11;18) in predicting the Hp-independence
will be both 80 – 90%. Ten – twenty per cent of enrolled patients will have CYP2C19 m1/m1,
m1/m2 or m2/m2 genotypes (considered as omeprazole poor metabolizer), and they might have
higher Hp eradication rate than those extensive metabolizers .