Ultra-low-dose radiation followed by orelabrutinib for early-stage MALT lymphoma

Ultra-low-dose Radiation Therapy Followed by Orelabrutinib as First-line Treatment for Stage Ⅰ-Ⅱ MALT Lymphoma: A Prospective, Multicenter Phase Ⅱ Study

This study will test whether a short course of very low-dose radiation followed by daily orelabrutinib helps adults with stage I–II MALT lymphoma keep their disease controlled with acceptable side effects.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Zhejiang Cancer Hospital (Academic / other)
• Drugs / interventions: rituximab, chemotherapy, radiation, orelabrutinib
• Locations: 2 sites (Hangzhou, Zhejiang and 1 other locations)
• Trial ID: NCT07554898 on ClinicalTrials.gov

What this trial studies

Participants receive ultra-low-dose radiation (4 Gy given as 2 Gy daily for 2 days) to the involved site, then begin oral orelabrutinib 150 mg once daily in 28-day cycles for up to six cycles, with the option to continue monotherapy for responders or those with stable disease up to 12 cycles. Eligible adults have histologically confirmed stage I–II MALT lymphoma with at least one measurable lesion, ECOG 0–1, adequate organ function, and no prior systemic anti-lymphoma therapy; gastric cases must be H. pylori–negative or refractory to eradication. Safety monitoring, tumor assessments, and follow-up visits are scheduled regularly, with long-term evaluations every three months to track durability of response and adverse events. The trial is multicenter and prospective, enrolling patients at participating hospitals in Zhejiang province and following predefined response and continuation rules.

Who should consider this trial

Good fit: Ideal candidates are adults (≥18 years) with histologically confirmed stage I–II MALT lymphoma with at least one measurable lesion, ECOG 0–1, adequate organ function, no prior systemic anti-lymphoma therapy, and for gastric cases either H. pylori negativity or failure of eradication therapy.

Not a fit: Patients with advanced (stage III–IV) disease, prior systemic anti-lymphoma therapy, poor organ function, ECOG >1, or only splenic involvement without measurable extranodal lesions are unlikely to meet eligibility or receive benefit from this regimen.

Why it matters

Potential benefit: If successful, this approach could provide durable control of localized MALT lymphoma with less intensive treatment and potentially fewer long-term toxic effects than conventional systemic therapy.

How similar studies have performed: Ultra-low-dose radiotherapy has shown good local control in indolent lymphomas and BTK inhibitors have activity in marginal zone lymphomas, but using ultra-low-dose radiation followed by orelabrutinib as first-line therapy is a relatively new combination that has not been widely tested.

Eligibility criteria

Inclusion Criteria:

1. Age ≥ 18 years, all genders eligible;
2. Histopathologically confirmed MALT lymphoma (extranodal marginal zone lymphoma) with at least one measurable lesion outside the spleen, with any diameter \> 1.0 cm;
3. No prior systemic anti-tumor therapy after diagnosis (including chemotherapy, targeted therapy, rituximab, etc.).

   Note: For patients with primary gastric MALT lymphoma, Helicobacter pylori (HP) must be negative or the patient must have failed standard HP eradication therapy. Patients with MZL who progressed or relapsed after local treatment (including surgery, Helicobacter pylori eradication, and hepatitis C treatment) are eligible for enrollment.
4. ECOG performance status score of 0-1;
5. Presence of treatment indications as judged by the investigator (including symptoms, cytopenias, risk of end-organ damage, bulky disease, or persistent progression);
6. Adequate major organ function, meeting the following criteria:

   1. Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, platelets ≥ 75 × 10⁹/L, hemoglobin ≥ 75 g/L; If bone marrow involvement is present: ANC ≥ 1.0 × 10⁹/L, platelets ≥ 50 × 10⁹/L, hemoglobin ≥ 50 g/L;
   2. Total bilirubin ≤ 1.5 × ULN, AST or ALT ≤ 2 × ULN, serum creatinine ≤ 1.5 × ULN, serum amylase ≤ ULN;
   3. International Normalized Ratio (INR) ≤ 1.5 × ULN.
7. Expected survival ≥ 3 months;
8. Voluntarily provide written informed consent before screening.

Exclusion Criteria:

1. Current or history of other malignant tumors, except for those who have achieved complete remission after radical treatment;
2. Lymphoma involvement of the central nervous system or transformation to high-grade lymphoma;
3. Patients with other tumors who have not recovered from non-hematologic toxicities of prior anti-tumor therapy to ≤ Grade 1 (except for alopecia);
4. Uncontrolled or significant cardiovascular diseases, including:

   1. Congestive heart failure of New York Heart Association (NYHA) Class II or above, unstable angina, myocardial infarction within 6 months before the first dose of the study drug, or arrhythmias requiring treatment at screening, or left ventricular ejection fraction (LVEF) \< 50%;
   2. Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, or unclassified cardiomyopathy);
   3. History of clinically significant QTc interval prolongation, or QTc interval at screening \> 470 ms for females or \> 450 ms for males;
   4. Subjects with symptomatic coronary artery disease requiring medication;
   5. Uncontrolled hypertension (despite lifestyle modification and use of a reasonable and tolerable maximum dose of 3 or more antihypertensive drugs \[including diuretics\] for more than 1 month, blood pressure still not reaching target, or blood pressure can only be effectively controlled with 4 or more antihypertensive drugs);
5. Active bleeding within 2 months before screening, or currently receiving anticoagulant drugs, or considered by the investigator to have a clear bleeding tendency;
6. Urine protein ≥ 2+ and 24-hour urine protein quantification ≥ 2 g/24 hours;
7. History of deep vein thrombosis or pulmonary embolism within the past 6 months;
8. History of organ transplantation or allogeneic hematopoietic stem cell transplantation;
9. Major surgery within 6 weeks before screening or minor surgery within 2 weeks before screening. Major surgery is defined as surgery performed under general anesthesia; however, diagnostic endoscopic procedures are not considered major surgery. Insertion of vascular access devices is exempt from this exclusion criterion;
10. HIV/AIDS or other serious infectious diseases;
11. Patients with severe pulmonary function impairment due to pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-induced pneumonitis, or other conditions;
12. Previous treatment with BTK inhibitors, BCR pathway inhibitors (e.g., PI3K, Syk), or BCL-2 inhibitors;
13. Subjects with drug abuse or alcohol abuse;
14. Pregnant or lactating women, or subjects of childbearing potential who are unwilling to use contraceptive measures;
15. Other conditions that, in the opinion of the investigator, make the subject unsuitable for participation in this trial.

Where this trial is running

Hangzhou, Zhejiang and 1 other locations

• No. 1, East Banshan Road , Gongshu District — Hangzhou, Zhejiang, China (Recruiting)
• The First Affiliated Hospital, Zhejiang University School of Medicine — Hangzhou, Zhejiang, China (Recruiting)

Study contacts

• Principal investigator: Yamin Tan, phD — Zhejiang Cancer Hospital
• Study coordinator: Xiaolin Yuan, MD

Conditions MALT Lymphoma