Study in Patients With Primary Breast Diffuse Large B-cell Lymphoma

Multi-center Phase II Study of the Combination of R-CHOP (RItuximab Plus Cyclophosphamide, Adriamycin, Vincristine, and Prednisolone) and Prophylactic Intrathecal Chemotherapy With Methotrexate in Patients With CD20+ Primary Breast Diffuse Large B-cell Lymphoma

The purpose of this study is to clarify the impact of rituximab on clinical outcomes in patients with primary breast diffuse large B-cell lymphoma and also to investigate the role of prophylactic intrathecal chemotherapy using methotrexate for reducing central nervous system (CNS) recurrence.

Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare presentation of non-Hodgkin's lymphoma. A significant risk of contralateral breast involvement and a tendency for central nervous system (CNS) progression have been identified in previous studies. Optimal treatment strategies for primary breast DLBCL have remained undefined, although the combination of anthracycline-based chemotherapy and radiotherapy may be considered to be the best treatment option in these studies. However, despite the administration of aggressive treatment, prognosis is still poor, even in localized disease, with 5-year progression-free survival rates of approximately 50% to 65% in most series. Therefore, other therapeutic options must be explored.

During the last decade, several studies have shown that rituximab plus CHOP or CHOP-like chemotherapy significantly improves clinical outcomes of patients with DLBCL. However, the relevance of rituximab in the management of this rare extranodal lymphoma has never been studied. Moreover, several studies have also suggested the possibility that prophylactic intrathecal chemotherapy might be effective in reducing CNS recurrence.

Thus, this trial is designed to prospectively evaluate the treatment strategy, which addressed the safety and efficacy of a combined therapy that included R-CHOP21 and prophylactic intrathecal chemotherapy using methotrexate.

Inclusion Criteria:

• Histologically confirmed CD20 positive primary breast DLBCL
• age ≤ 70
• No prior chemotherapy or radiotherapy for DLBCL
• Performance status (ECOG) ≤ 2
• Cardiac ejection fraction ≥ 50 % as measured by MUGA or 2D ECHO without clinically significant abnormalities
• Adequate renal function: serum creatinine level < 2 mg/dL (177 μmol/L)
• Adequate liver functions: Transaminase (AST/ALT) < 3 X upper normal value, Bilirubin < 2 X upper normal value
• Adequate BM functions: hemoglobin ≥ 9 g/dL absolute neutrophil count (ANC) ≥ 1,500/μL and platelet count ≥ 75,000/μL
• A negative serum or urine pregnancy test prior to treatment must be available both for pre menopausal women and for women who are < 1 years after the onset of menopause
• Life expectancy more than 6 months
• Informed consent

Exclusion Criteria:

• other subtype primary breast non-Hodgkin's lymphoma than DLBCL

• secondary breast DLBCL

• Patients with a known history of HIV seropositivity or HCV (+). Patients who have HBV (+) are eligible. However, primary prophylaxis using antiviral agents (i.e. lamivudine) is recommended for HBV carrier to prevent HBV reactivation during whole treatment period.

• Any other malignancies within the past 5 years except curatively treated non-melanoma skin cancer or in situ carcinoma of cervix uteri

• Pregnant or lactating women, women of childbearing potential not employing adequate contraception

• Other serious illness or medical conditions

  • Unstable cardiac disease despite treatment, myocardial infarction within 6 months prior to study entry
  • History of significant neurologic or psychiatric disorders including dementia or seizures
  • Active uncontrolled infection (viral, bacterial or fungal infection)
  • Other serious medical illnesses

• Known hypersensitivity to any of the study drugs or its ingredients (i.e., hypersensitivity to Polysorbate 20, CHO cell products, or recombinant human antibodies)

• Concomitant administration of any other experimental drug under investigation, or concomitant chemotherapy, hormonal therapy, or immunotherapy