Pembrolizumab in MarginalzoneLymphoma A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY

Inclusion Criteria: Patients must have a proven pathological diagnosis of MZL, diagnosed by a reference pathology center. Patients must meet the following inclusion criteria to be eligible for participation in this study: * Confirmed CD20 positive de novo or relapsed MALT Lymphoma in need of treatment following or being not eligible for local therapy (including surgery, radiotherapy and antibiotics e.g. for H. pylori-positive gastric lymphoma arisen at any extranodal site) OR * Confirmed CD20 positive de novo or relapsed splenic MZL in need of treatment following or not being eligible for local therapy (including surgery and antiviral therapy for Hepatitis C Virus) OR * Confirmed CD20 positive de novo or relapsed nodal MZL in need of treatment following or not being eligible for local therapy (radiotherapy). The need of treatment is applicable in the case of B symptoms, deterioration of peripheral blood counts due to lymphoma infiltration of the bone marrow, rapid enlargement of lymph nodes or compression of vital organs by bulky disease. For nodal MZL and extragastric MALT lymphoma: • At least one bi-dimensionally measurable lesion (\>=1.5 cm in its largest dimension by CT/PET-CT scan or MRI) For splenic MZL (SMZL): In patients with splenic MZL, an enlarged spleen on CT scan and lymphoma cell infiltration has to be seen in bone marrow and/or peripheral blood. At least one of the following criteria must be fulfilled: * Bulky progressive or painful splenomegaly * one of the following symptomatic/progressive cytopenias: Hb \< 10 g/dL, or Platelet count \< 80.000 /µL, or neutropenia \< 1000 /µL, whatever the reason (autoimmune or hypersplenism or bone marrow infiltration) * splenectomised patients with rapidly raising lymphocyte counts, development of lymphadenopathy or involvement of extranodal sites if not being eligible for local therapy * SMZL with concomitant hepatitis C infection which has not responded to or has relapsed after Interferon and/or Ribavirin and/or direct antiviral agents (patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA) For gastric MALT Lymphoma: For gastric MALT lymphoma, the clinical evidence of the MZL as seen by gastroendoscopy is sufficient. There is no need to show a measurable lesion by CT scan or MRI. Inclusion is possible for patients with: * H. pylori-negative cases following or being not eligible for local therapy (i.e., surgery, radiotherapy or antibiotics) or after systemic therapy * H. pylori-positive disease that has remained stable, progressed, or relapsed following antibiotic therapy Others: * Age ≥ 18 years * Life expectancy \> 3 months * Meet the following pretreatment laboratory criteria at the Screening visit conducted within 28 days of study enrollment (unless due to underlying lymphoma): * Baseline platelet count ≥ 75 x 109/L (if not due to BM infiltration by the lymphoma), absolute neutrophil count ≥ 1.5 x 109/L. * Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks) * International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants * ASAT (SGOT): ≤ 2.5 times the upper limit of institutional laboratory normal value or ≤ 5 times the upper limit of institutional laboratory normal value in subjects with lymphoma in the liver. * ALAT (SGPT): ≤ 2,5 times the upper limit of institutional laboratory normal value or ≤ 5 times the upper limit of institutional laboratory normal value in subjects with lymphoma in the liver * Serum total bilirubin: ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 ULN (unless clearly related to the disease) * Serum creatinine ≤ 1.5 × ULN OR ≥ 60 mL/min GFR or CrCl for subjects with creatinine levels \> 1.5 × institutional ULN * Negative HIV antibody * Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing to undergo monthly DNA testing. Patients who have protective titers of HBSAb after vaccination or prior but cured hepatitis B are eligible. * Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. * For women of child-bearing potential only: Pregnancy β-HCG negative. Serum or urine β-HCG must be negative during screening and at study enrolment visit. * Premenopausal fertile females must agree to use a highly effective method of birth control for the duration of the therapy up to 12 months after the last dose of Rituximab and through 4 months after the last dose of Pembrolizumab. A highly effective method of birth control is defined as those which results in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable or implantable), intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomised partner or sexual abstinence. Contraception and pregnancy testing are required according the CTFG recommendations (http://www.hma.eu/fileadmin/dateien/Human\_Medicines/01-About\_HMA/Working\_Groups/CTFG/2014\_09\_HMA\_CTFG\_Contraception.pdf) * Men must agree not to father a child for the duration of therapy and 6 months after and must agree to advice a female partner to use a highly effective method of birth control. According to CTFG recommendations, men must use condoms. * Willingness and ability to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions * Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, possible side effects, potential risks and discomforts, and other pertinent aspects of study participation Exclusion Criteria: The presence of any of the following will exclude a subject from enrolment: * ECOG performance status ≥ 2 * History of a malignancy except for the following: adequately treated local basal cell or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial bladder cancer, asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate specific antigen for ≥ 1 year prior to study enrolment visit, other malignancy treated with a curative intent and currently in complete remission, for ≥ 3 years * Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma * Has had prior chemotherapy (systemic anti-cancer therapy), targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or baseline value) from AEs due to a previously administered agent * Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study * Note: If a subject received major surgery, they must have recovered adequately from complications from the intervention prior to starting therapy * Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of study enrolment visit * Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cholangitis, extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension * Treatment with any other investigational agent or participating in another clinical trial with an investigational product within 4 weeks prior to entering this study or within 5 x the half-life (t1/2) of the investigational product, whichever is longer * Breastfeeding or Pregnancy * Congestive heart failure \> New York Heart Association (NYHA) class 2 * Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) * Myocardial infarction less than 6 months before start of study medication * Uncontrolled arterial hypertension despite optimal medical management * Prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in the investigator's opinion, could adversely affect the safety of the subject or impair the assessment of study results * Vaccination with a live vaccine within 30 days prior to start of therapy * Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication * Non-healing wound, ulcer, or bone fracture * History or concurrent interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator) * Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) * Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease * Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study treatment * Has a history of non-infectious pneumonitis that required steroids, or current pneumonitis * History of anaphylaxis in association with previous administration of monoclonal antibodies or severe hypersensitivity (≥Grade 3) to the investigational medicinal products and/or any of its excipients * Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment * Has a known history of active TB (Bacillus Tuberculosis) * Medical history of allogeneic stem cell transplant * Ongoing alcohol or drug addiction or known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial * Diagnosis of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN)