BENdamustine at Elevated Dose for Relapsed Follicular Lymphoma in Intensification Therapy and Transplantation (BENEFIT)

A Multicenter Phase II Study Evaluating BeEAM (Bendamustine, Etoposide, Cytarabine, Melphalan) Prior to Autologous Stem Cell Transplant for First and Second Chemosensitive Relapses in Patients With Follicular Lymphoma

The purpose of this study is to evaluate the efficacy and safety of BeEAM (bendamustine, etoposide, cytarabine and melphalan) regimen prior to autologous stem cell transplant for first and second chemosensitive relapses in patients with follicular lymphoma (World Health Organisation (WHO) grade 1, 2, 3a).

The natural history of this follicular lymphoma (FL) is marked by multiple relapses. The prognosis of FL has improved with the use of effective sequential chemotherapy and the introduction of anti-cluster of differentiation antigen 20 (anti-CD20) monoclonal antibody. Based on the multiple phases II, high dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) appear to be an effective treatment in relapsed FL. At rituximab era, the 3-years EFS rate was 75% for relapsed transplanted patients treated in first line therapy in FL2000 protocol. Bendamustine that combines alkylating and antimetabolite activities had proven clinical activity in relapse and in first line therapy of FL. Carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM regimen) is one of the most used schedule of HDT in non hodgkin lymphoma. Regarding the good safety profile of Bendamustine, Visani et al. proposed a phase I/II of bendamustine at day -7 and -6, followed by etoposide, cytarabine and melphalan with similar dose than BEAM regimen. The bendamustine maximal dose is 200 mg/m² day -7, -6. Data from engraftment showed closed results than those observed after BEAM. None of patients experienced a dose limiting toxicity. In this context, the investigators proposed to perform a multicentric phase II of this regimen with 200 mg/m² day-7 and -6 of bendamustine for first and second relapsed FL with a chemosensitive disease after salvage therapy. No FL was evaluated in Visani et al. study. In addition, the investigators can observe a shortage of the BCNU these last years that incline to evaluate new schedule of HDT.

INCLUSION CRITERIA:

• Histologically confirmed follicular lymphoma relapsed (WHO grade 1, 2, 3a)

• Patients aged from 18 to 65 years

• First or second chemosensitive relapses after salvage therapy (rituximab-chemotherapy) based on 2007 Cheson et al. international response criteria (CR and PR) before the decision of BeEAM (HDT) and ASCT (autologous stem cell transplantation) treatment

• Eligible for ASCT

• Autologous graft with a minimum of a number of cluster of differentiation 34 (CD34+) cells 3.0x106/kg.

• Autologous transplantation will be performed in hematopoietic stem cell transplantation authorized centers.

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 to 2

• Minimum life expectancy of 3 months

• Cardiovascular baseline corrected QT interval F ( QTcF) ≤ 450 msec (male) or 470 msec (female)

• Medications that may cause corrected QT interval (QTc) interval prolongation should be avoided by patients entering on trial

• Normal organ and marrow function as defined below:

  • Absolute neutrophil count ≥ 1.5 G/l
  • Platelet count ≥ 100 G/l or > 75 G/l if the bone marrow is involved
  • Creatine clearance ≥ 50 ml/min
  • Serum Glutamate Oxaloacetate Transaminase (SGOT) and Serum Glutamate Pyruvate Transaminase (SGPT) ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5 x ULN if liver metastasis
  • Total bilirubin ≤ 1.5 x ULN

• Cardiac ejection fraction greater than 50% by echocardiogram or multiple gated acquisition scan (MUGA scan)

• Negative serum pregnancy test for women of childbearing potential*

• Pregnancy tests will include a negative serum pregnancy test (with a sensitivity of at least 25 mill-International Unit (mIU)/ml)

• Women of childbearing potential* and men must agree to use adequate contraception prior to study entry, for the duration of study participation and until 6 months after the end of treatment

  • Female patients who meet at least one of the following criteria are defined as women of non-childbearing potential:
  • ≥ 50 years old and naturally amenorrheic for ≥ 1 year
  • Permanent premature ovarian failure confirmed by a specialist gynecologist
  • Previous bilateral oophorectomy
  • XY genotype, Turner's syndrome or uterine agenesis
  • Female patients who do not meet at least of the above criteria are defined as women of childbearing potential

• Ability to understand and willingness to sign a written informed consent document

• Covered by a medical insurance

• Signed informed consent

EXCLUSION CRITERIA:

• Transformed follicular lymphoma
• Prior autologous or allogeneic transplantation
• Presence of a none chemosensitive disease before HDT according to 2007 Cheson et al. international response criteria (stable or progressive disease)
• Contraindication to any drug contained in the chemotherapy regimens
• Bone marrow infiltration > 25% before HDT+ASCT
• Positive HIV, Hepatitis C Virus (HCV) and Hepatitis B (HBs)Ag serologies
• Current bacterial, viral or fungal infection
• Treatment with any investigational drug within 30 days before enrolment
• Major surgery within 30 days before enrolment
• Participation in another clinical trial within 30 days prior to enrolment in the study and during study
• Any serious active disease or co-morbid medical conditions that would interfere with therapy
• Prior history of malignancies other than lymphoma (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast) unless the subject has been free of the disease for ≥ 5 years
• Known or suspected hypersensitivity to any of the agents or excipients of the regime under evaluation
• Concomitant treatment with chemotherapy or immunotherapy or radiotherapy
• Yellow fever vaccination (attenuated virus vaccine )
• Pregnant or lactating female
• Abnormalities in cardiac function or clinically significant heart disease such as acute myocardial infarction or unstable angina within 6 months prior to the start of study treatment, heart failure New York Heart Association (NYHA) class III or IV, uncontrolled hypertension or a history of antihypertensive treatment poor compliance, uncontrolled arrhythmias with treatment, except extrasystoles or minor conduction disorders
• Known involvement of the central nervous system by lymphoma
• History of chronic liver disease
• History of hepatic veno-occlusive disease (VOD) or sinusoidal obstruction syndrome (SOS)
• Excessive alcohol use