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Recently, the availability of R has substantially changed therapeutic approach to FL patients, since its combination with chemotherapy has improved response rates, progression free survival (PFS) and overall survival (OS). Based on the results of recently completed randomized studies the standard treatment for patients with FL should consist of an initial therapy with R-CHOP combination followed by two-year maintenance with R. Although results of randomized trials confirmed that this approach results in an improved patients' outcome and made a step forward in the management of patients with FL, one important question that can be raised is if this approach is really needed for all patients with FL or if some of them could benefit from a reduced intensity treatment achieving the same results in terms of outcome and survival . This question is of particular interest for newly diagnosed patients for whom maintenance does not affect OS.
More recent data demonstrated that the outcome of patients with FL can be further predicted by evaluating the quality of response to therapy studying minimal residual disease (MRD). This project addresses the objective of evaluating if combining clinical response assessed on FDG-PET scan and molecular response measured through MRD detection could permit to single out groups of patients at different risk of progression and to consequently modulate maintenance therapies, with the aim to provide clinicians a more rational use of the available diagnostic and therapeutic resources.
Full description
This is a multicenter, randomized, phase III, superiority study comparing standard vs response driven approach to maintenance. Adult patients (age ≥ 18 years) with naïve, untreated follicular lymphoma, stage II-IV, Follicular Lymphoma International Prognostic Index 2 (FLIPI2) >0 requiring a therapeutic intervention will be recruited and randomly assigned in a 1:1 ratio to either standard or experimental arm.
All patients will receive the same induction therapy with 6 cycles of R-CHOP or R-bendamustine and 2 additional doses of Rituximab.
At baseline patients will be assessed for molecular status and staged by means of CT scan. A baselineFluorine-18-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) scan should also be performed.
At the end of chemoimmunotherapy all patients will be assessed for disease response by common clinical and laboratory examination, CT scan and FDG-PET. An intermediate assessment of response with CT scan and FDG-PET (optional) will also be performed after the first four courses of R-chemoimmunotherapy.
At the end of induction therapy the status of minimal residual disease will be also evaluated.
After induction treatment all responding patients in the standard arm will receive standard maintenance therapy with Rituximab (every 2 months for 2 years), while patients in the experimental arm will be subdivided into two risk groups and assigned to different post induction treatments based on FDG-PET and MRD results. In both arms, patients with stable or progressive disease (PET positive and less than PR on CT scan) will be addressed to salvage treatment chosen at physician discretion.
In the experimental arm, risk group allocation will be performed primarily on the basis of FDG-PET results:
Patients at low risk (FDG-PET negative) will received maintenance therapy according to their MRD status,particularly:
Patient at high risk (FDG-PET positive) will receive maintenance regardless of their MRD status:
· Group 2: intensified maintenance ((90)Y Ibritumomab Tiuxetan + Rituximab maintenance )
Enrollment
Sex
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Volunteers
Inclusion criteria
Histological diagnosis of B-Cell CD20+ Follicular Lymphoma (FL), grade I, II, IIIa according to the WHO 2008 classification
ECOG performance status 0-2
Age ≥ 18 years
Ann Arbor stage II-IV
FLIPI2>0
Presence of evaluable/measurable disease after diagnostic biopsy
At least one of the following criteria for defining active disease:
Life expectancy > 6 months
Left ventricular ejection fraction (LVEF) ³ 50%
Serum negativity for HIV
Serum negativity for HBsAg; HBcAb positive but HBV-DNA negative patients are allowed with mandatory Lamivudine prophylaxis.
Serum negativity for HCV, except for those patients without signs of active viral replication assessed by HCV-RNA copies
Serum creatinine < 2mg/dl , serum bilirubin < 1.5mg/dl, aspartate amino-transferase (AST/GOT) £ 2.5xUNV, alanine amino-transferase (ALT/GPT) £ 2.5xUNV, and alkaline phosphatase £ 4 times the upper limit of normal (unless the increase is attributed directly to the presence of tumour by the Investigator)
Patients with no previous treatment for the lymphoma with the exception of locoregional radiotherapy (IFRT)
Adequate measure adoption to avoid pregnancy
Written informed consent given at time of registration
Patient must be accessible for treatment and follow up.
Exclusion criteria
Histological diagnosis of :
Ann Arbor stage I
Suspect or clinical evidence of CNS involvement by lymphoma
History of other malignancies within 5 years prior to study entry except for adequately treated carcinoma in situ of the cervix or basal or squamous cell skin cancer, low grade, early stage localized prostate cancer treated surgically with curative intent, good prognosis DCIS of the breast treated with lumpectomy alone with curative intent
Evidence of any severe active acute or chronic infection
Concurrent co-morbid medical condition which might exclude administration of full dose chemotherapy
Severe chronic obstructive pulmonary disease with hypoxemia
Severe diabetes mellitus difficult to control with adequate insulin therapy
Myocardial infarction within 6 months before study entry
Clinically significant secondary cardiovascular disease e.g. uncontrolled hypertension, (resting diastolic blood pressure >115 mmHg), uncontrolled multifocal cardiac arrhythmias, symptomatic angina pectoris or congestive cardiac failure NYHA class III-IV
HbsAg-positive, HIV-positive, or HCVAb-positive patients
Known hypersensitivity or anaphylactic reactions to murine antibodies or proteins
Any other co-existing medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent
Follicular lymphoma, showing a negative baseline PET scan.
Primary purpose
Allocation
Interventional model
Masking
807 participants in 4 patient groups
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Data sourced from clinicaltrials.gov
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