Bendamustine and Rituximab for the Treatment of Splenic Marginal Zone Lymphoma

Study Overview
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Brief Summary
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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.

Detailed Description
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Prospective, multicenter, open-label, phase II study, designed to determine efficacy and safety of a Chemo-immunotherapy with the combination of bendamustine + rituximab in patients with splenic marginal zone lymphoma. Study Population: previously untreated (except for splenectomy and/or antiviral therapy for Hepatitis C Virus (HCV) infection) and symptomatic Splenic Marginal Zone patients. Objectives: evaluation of the efficacy and the safety of R-Bendamustine in symptomatic Splenic Marginal Zone Lymphoma patients. Primary Objective: efficacy of R-Bendamustine measured by Complete Response rate. Complete response rate defined as regression to normal size on CT of organomegaly (spleen, liver, lymph nodes); normalization of the blood counts and no evidence of circulating clonal cells, and no evidence or minor (≤ 5%) Bone Marrow (BM) infiltration detected by immunohistochemistry (IHC). Treatment: The R-Bendamustine regimen consisted of 28-day cycle. Patients achieving a complete response (CR) after 3 cycles received only one more cycle of R-Bendamustine, while those achieving a partial response (PR) received 3 additional cycles of R-Bendamustine; if less than PR patients were withdrawn from the study

Official Title
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Bendamustine and Rituximab for the Treatment of Splenic Marginal Zone Lymphoma. The International Extranodal Lymphoma Study Group (IELSG) 36 Phase II Prospective Study

Conditions
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Marginal Zone B-cell Lymphoma

Intervention / Treatment
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* Drug: Bendamustine and Rituximab


Participation Criteria
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Eligibility Criteria
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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. If patients not splenectomised: diagnosis on bone marrow biopsy (histology and immunohistochemistry), and blood (cytology, immunophenotype), chromosomal abnormalities by QMPSF optional. 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: Symptomatic SMZL in not splenectomized patients 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 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 SMZL with enlarged lymphoadenopathy or involvement of extranodal sites with or without cytopenia Symptomatic disease in SMZL splenectomised patients with rapidly raising lymphocyte counts, development of lymphadenopathy or involvement of extranodal sites. 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: Absolute neutrophil count (ANC) ≥1.000/mm3 and Platelets ≥100.000/mm3, unless these abnormalities are related to bone marrow infiltration or to hypersplenism. Aspartate transaminase (AST) ≤2 x upper limit of normal (ULN); Alanine transaminase (ALT) ≤2 x ULN; total bilirubin ≤1.5 x ULN. Creatinine clearance ≥ 10 ml/min (as calculated by the Cockcroft-Gault formula) All patients must: Agree to abstain from donating blood while taking study drug therapy and following discontinuation of study drug therapy. Agree not to share study medication with another person. 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. 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: Any type of lymphoma other than SMZL. Patients with proven biopsy of histological transformation. Contraindication to any drug contained in the chemotherapy regimen. Myocardial infarction during last 3 months or unstable coronary disease or uncontrolled chronic symptomatic congestive heart insufficiency NYHA III - IV. Uncontrolled hypertension. Uncontrolled diabetes mellitus as defined by the investigator. Active systemic infection requiring treatment. Previously known HIV positive serology. 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). Active and previously untreated HCV infection. 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. Major surgery within 30 days before the inclusion in the study A positive Coombs test without haemolysis or an autoimmune hemolytic anemia is not an exclusion criterion. Impaired renal function with creatinine clearance <10 ml/min. Severe chronic obstructive pulmonary disease with hypoxemia. Medical condition requiring long-term use (>1 months) of systemic corticosteroids. Serious medical or psychiatric illness likely to interfere with participation in this clinical study. Prior participation in another study with experimental drug during the last 4 months. Pregnant or currently breast-feeding woman.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bendamustine and Rituximab<br>Induction Phase (Cycle 1 to Cycle 3 ): Bendamustine 90 mg/sqm i.v. d1 & d2* Rituximab 375 mg/m2 i.v. d1** Extended Phase (Cycle 4 to Cycle 6): Bendamustine 90 mg/sqm i.v. d1 & d2* Rituximab 375 mg/m2 i.v. d1 From Cycle 4 to Cycle 6, every 4 weeks, depending on the response after the first 3 Cycles *Or days 2-3 according to institutional/patient/physician preference **Administration of Rituximab during cycle 1 and cycle 2 can be postponed to day 8 or 14 in case of risk of tumor lysis syndrome (TLS) | Drug: Bendamustine and Rituximab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate (CRR) | Percentage of patients with complete response. Complete response to be assessed by means of CT-scan, Immunophenotype in blood and bone marrow (PET-scan optional) Complete response (CR) requires the disappearance of all evidence of disease Regression to normal size on CT of organomegaly (splenomegaly, hepatomegaly and lymphoadenopathies) Normalization of the blood counts (Hb >12 g/dl; platelets >100.000/mm3; neutrophils >1.500/mm3 and no evidence of circulating clonal B-cells) No evidence or minor (<5%) BM infiltration detected by immunohistochemistry | At the end of treatment (After 24 weeks of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Percentage of patients with complete and partial response. Partial response (PR) requires regression of 50% or greater in the measurable disease manifestations and no new sites of disease. This should include: resolution or decrease in spleen size, improvement on cytopenias and resolution or decrease in lymphadenopathy if present. Bone Marrow should show a decrease in the level of lymphoid infiltration and improvement of the haemopoietic reserve | At the end of treatment (After 24 weeks of treatment) | 
| 3-year Progression Free Survival (PFS) | Percentage of patients free from disease progression after 3 years from study entry. Progression is defined as reappearance of cytopenia or lymphoma relapse/ progression with enlarged lymph node(s) or spleen if present, histologic transformation or death as a result of any cause. | 3 years after study entry | 
| 3-years Duration of Response (DOR) | Percentage of responding patients after 3 years from study entry. DOR is defined for all patients who achieved a response (CR and PR) | 3 years from study entry | 
| 3-years Event Free Survival (EFS) | Percentage of patients free from events after 3 years from study entry. Events are defined as any treatment failure including disease progression, or discontinuation of treatment for any cause (eg, disease progression, toxicity, patient preference, initiation of new treatment without documented progression, or death). | 3 years after study entry | 
| 3-years Overall Survival Rate | Percentage of patients alive after 3 years from study entry | 3 years after treatment start | 
| 5 Years Progression Free Survival (PFS) - | Percentage of patients free from disease progression after 5 years from treatment start. Progression is defined as reappearance of cytopenia or lymphoma relapse/ progression with enlarged lymph node(s) or spleen if present, histologic transformation or death as a result of any cause. | Five years after study entry | 
| 5 Years Overall Survival (OS) | Percentage of patients alive after 5 years from study entry | Five years after study entry |