Bendamustine and Rituximab for the Treatment of Splenic Marginal Zone Lymphoma
Condition: Marginal Zone B-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell, Marginal Zone
Intervention: Bendamustine and Rituximab
Intervention MeSH terms: Rituximab; Bendamustine Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 78.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No

Summary:

      Splenic Marginal Zone Lymphoma (SMZL) is a well-defined low-grade B-cell lymphoma,considered
      as a rare neoplasm accounting for about 2% of all non-Hodgkin's lymphomas (NHL) and
      represents for most cases of otherwise unclassifiable chronic lymphoid B-cell cluster of
      differentiation antigen 5 (CD5)-lymphoproliferative disorders. SMZL is characterized by an
      almost exclusive involvement of the spleen and bone marrow and in about 25% of cases the
      disease pursues an aggressive course and most patients die of lymphoma progression within 3-4
      years.

      Retrospective studies have indicated that purine analogous achieved very high response rates
      in both naïve and pre-treated patients. Moreover, the introduction of the anti-cluster of
      differentiation antigen 20 (CD20) humanized antibody rituximab, either used alone or in
      combination with chemotherapy has been reported to be very effective in producing a rapid
      clearance of neoplastic cells.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Initial diagnosis of CD20+ Splenic Marginal Zone Lymphoma morphology confirmed by
             histology, cytology, immunophenotype (chromosomal abnormalities by quantitative
             multiplex Polymerase Chain Reaction (PCR) of short fluorescent fragments (QMPSF) is
             optional) according to World Health Organization (WHO) 2008 classification of Lymphoma
             criteria or according to the recommendation of the Splenic Lymphoma Group for non
             splenectomized patient.

               1. If patients not splenectomised: diagnosis on bone marrow biopsy (histology and
                  immunohistochemistry), and blood (cytology, immunophenotype), chromosomal
                  abnormalities by QMPSF optional.

               2. If patients splenectomised diagnosis on spleen, bone marrow biopsy (histology and
                  immunohistochemistry), and blood (cytology, immunophenotype) chromosomal
                  abnormalities by QMPSF optional.

          -  No previous treatment with immunotherapy or chemotherapy or radiotherapy unless
             pretreatment by mono corticotherapy.

          -  Patients requiring a treatment with at least one of the following situation:

               1. Symptomatic SMZL in not splenectomized patients

                    1. Bulky (arbitrarily defined as ≥6 cm below left costal margin) or progressive
                       or painful splenomegaly, without enlarged lymphoadenopathy, with or without
                       cytopenia, not eligible for splenectomy or not willing splenectomy

                    2. One of the following symptomatic/progressive cytopenias: Hb <10 g/dL, or
                       Plat <80.000/mm3, or ANC <1.000/mm3, whatever the reason (autoimmune or
                       hypersplenism or bone marrow infiltration) not eligible for splenectomy or
                       not willing splenectomy

                    3. SMZL with enlarged lymphoadenopathy or involvement of extranodal sites with
                       or without cytopenia

               2. Symptomatic disease in SMZL splenectomised patients with rapidly raising
                  lymphocyte counts, development of lymphadenopathy or involvement of extranodal
                  sites.

               3. SMZL with concomitant hepatitis C infection who have not responded or are
                  relapsed after Interferon and/or Ribavirin.

          -  Clinically and/or radiologically confirmed measurable disease before treatment start.

          -  Aged ≥ 18 yo at time of initial diagnosis and ≤ 80 yo.

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2

          -  Minimum life expectancy of >6 months.

          -  Voluntary signed informed consent before performance of any study related procedure
             not part of normal medical care, with the understanding that consent may be withdrawn
             by the patient at any time without prejudice to future medical care.

          -  The following laboratory values at screening:

               1. Absolute neutrophil count (ANC) ≥1.000/mm3 and Platelets ≥100.000/mm3, unless
                  these abnormalities are related to bone marrow infiltration or to hypersplenism.

               2. Aspartate transaminase (AST) ≤2 x upper limit of normal (ULN); Alanine
                  transaminase (ALT) ≤2 x ULN; total bilirubin ≤1.5 x ULN.

               3. Creatinine clearance ≥ 10 ml/min (as calculated by the Cockcroft-Gault formula)

        All patients must:

          1. Agree to abstain from donating blood while taking study drug therapy and following
             discontinuation of study drug therapy.

          2. Agree not to share study medication with another person.

          3. Agree to use an adequate method of contraception for women of childbearing potential
             during the study treatment and until 12 months after the end of the study treatment.

          4. Agree to use an adequate method of contraception for men during the study treatment
             and until 6 months after the end of the study treatment

        Exclusion Criteria:

          1. Any type of lymphoma other than SMZL.

          2. Patients with proven biopsy of histological transformation.

          3. Contraindication to any drug contained in the chemotherapy regimen.

          4. Myocardial infarction during last 3 months or unstable coronary disease or
             uncontrolled chronic symptomatic congestive heart insufficiency NYHA III - IV.

          5. Uncontrolled hypertension.

          6. Uncontrolled diabetes mellitus as defined by the investigator.

          7. Active systemic infection requiring treatment.

          8. Previously known HIV positive serology.

          9. Active hepatitis B virus infection (presence of antigen HBS+; in case of presence of
             antibody anti HBC+ and anti HBS+, controls should be organized according to guidelines
             of AASLD and l'EASL).

         10. Active and previously untreated HCV infection.

         11. Prior history of malignancies other than lymphoma within 3 years (except for complete
             resection of basal cell carcinoma, squamous cell carcinoma of the skin, or in situ
             malignancy). Patients previously diagnosed with prostate cancer are eligible if (1)
             their disease was T1-T2a, N0, M0, with a Gleason score </=7, and a prostate specific
             antigen(PSA) </=10 ng/mL prior to initial therapy, (2) they had definitive curative
             therapy (ie, prostatectomy or radiotherapy) >/=2 years before Day 1 of Cycle 1, and
             (3) at a minimum 2 years following therapy they had no clinical evidence of prostate
             cancer, and their PSA was undetectable if they underwent prostatectomy or <1 ng/mL if
             they did not undergo prostatectomy.

         12. Major surgery within 30 days before the inclusion in the study

         13. A positive Coombs test without haemolysis or an autoimmune hemolytic anemia is not an
             exclusion criterion.

         14. Impaired renal function with creatinine clearance <10 ml/min.

         15. Severe chronic obstructive pulmonary disease with hypoxemia.

         16. Medical condition requiring long-term use (>1 months) of systemic corticosteroids.

         17. Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

         18. Prior participation in another study with experimental drug during the last 4 months.

         19. Pregnant or currently breast-feeding woman.