title: Lenalidomide maintenance in patients with relapsed diffuse large B-cell lymphoma who are not eligible for autologous stem cell transplantation: an open label, single-arm, multicentre phase 2 trial.
abstract: BACKGROUND
  Patients with relapsed diffuse large B-cell lymphoma (DLBCL) not eligible for autologous stem cell transplantation (ASCT) or having relapse after ASCT have a low likelihood of cure. Single-drug maintenance after salvage therapy might be an attractive strategy to prolong survival in these patients. Lenalidomide is a suitable candidate for long-lasting maintenance as it is an oral drug, active against DLBCL that can be taken for years with an acceptable toxicity profile. We designed a study to investigate safety and efficacy of lenalidomide maintenance in patients with chemosensitive relapse of DLBCL not eligible for ASCT or having relapse after ASCT.
  
  
  METHODS
  In this open-label, single group, multicentre phase 2 trial, we recruited HIV-negative adults with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy from 12 oncology-haematology centres in Italy. All patients were given oral lenalidomide 25 mg per day for 21 of 28 days until lymphoma progression or unacceptable toxicity (severely compromises organ function, quality of life, or both). Primary endpoint was 1-year progression-free survival. The estimated sample size was 47 patients; maintenance was deemed efficacious if at least 19 patients were progression-free survivors at 1 year. All enrolled patients were included in primary analyses, with the exception of patients who post-hoc objectively did not meet the eligibility criteria (modified intention-to-treat). This study is registered with clinicaltrials.gov registry, number NCT00799513.
  
  
  RESULTS
  Between March 24, 2009, and Dec 22, 2015, we recruited 48 patients. 46 of 48 enrolled patients were assessable (two patients had unconfirmed diagnoses). 36 (78%) of 46 patients had de novo DLBCL and ten (22%) of 46 patients had transformed DLBCL. At a median follow-up of 25 months (IQR 12-56), 556 lenalidomide courses had been delivered, with an average mean of 12 courses (range 3-41) per patient; 19 patients were still in treatment at a median follow-up of 25 months. Lenalidomide was well tolerated; with the exception of neutropenia, grade 3-4 toxicities were uncommon. We recorded ten severe adverse events in nine patients due to febrile neutropenia (n=4), diarrhoea (n=2), melena, stroke, vomiting, and intestinal infarction; all but one patient recovered, and six of these patients continued with lenalidomide treatment. The exception was the only death due to toxicity (intestinal infarction). At 1 year from trial registration, 28 patients were progression free, which was much higher than the predetermined efficacy threshold. During the whole observation period, 21 events occurred: progressive lymphoma in 19 patients, death due to toxicity in one, death while off therapy in one, 1-year progression-free survival was 70% (95% CI 57-83).
  
  
  CONCLUSIONS
  With the limitations of a non-randomised design, this trial supports the use of lenalidomide maintenance in patients with chemo-sensitive relapse of DLBCL who are not eligible for ASCT or who had relapse after ASCT. These results warrant further investigation of immunomodulatory drugs as maintenance in high-risk patients with DLBCL.
  
  
  BACKGROUND
  Celgene Corp.
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, Milan, Italy. Electronic address: ferreri.andres@hsr.it.
authors.forename: Andrés J M
authors.initials: AJ
authors.lastname: Ferreri
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, Milan, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sassone
authors.affiliation: Centro Trapianti e Terapie Cellulari "Carlo Melzi", A O Universitaria S. Maria Misericordia, Udine, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Zaja
authors.affiliation: Division of Hematology, Spedali Civili, Brescia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Re
authors.affiliation: Division of Medical Oncology, National Cancer Institute, Aviano, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Spina
authors.affiliation: Division of Hematology, University Sapienza, Rome, Italy.
authors.forename: Alice Di
authors.initials: AD
authors.lastname: Rocco
authors.affiliation: Azienda Ospedaliera Università Senese, Siena, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Fabbri
authors.affiliation: Division of Hematology, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Stelitano
authors.affiliation: Division of Hematology, San Bortolo Hospital, Vicenza, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Frezzato
authors.affiliation: Division of Hematology, Niguarda Hospital, Milan, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Rusconi
authors.affiliation: Division of Hematology, Azienda Ospedaliera di Padua, University of Padua, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Zambello
authors.affiliation: Celgene, San Diego, CA, USA.
authors.forename: Suzana
authors.initials: S
authors.lastname: Couto
authors.affiliation: Celgene, San Diego, CA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Oncology and Hematology; G. da Saliceto Hospital, Piacenza, Italy.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Arcari
authors.affiliation: U O di Oncologia ed Ematologia Oncologica, Ospedale di Mirano, Mirano, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertoldero
authors.affiliation: University Centre for Statistics in the Biomedical Sciences (CUSSB), Vita-Salute San Raffaele University, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Nonis
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, Milan, Italy.
authors.forename: Lydia
authors.initials: L
authors.lastname: Scarfò
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, Milan, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Calimeri
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Cecchetti
authors.affiliation: Centro Trapianti e Terapie Cellulari "Carlo Melzi", A O Universitaria S. Maria Misericordia, Udine, Italy.
authors.forename: Marianna
authors.initials: M
authors.lastname: Chiozzotto
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, Milan, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Govi
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Hematology, Milan, Italy; Vita-Salute San Raffaele University, Pathology Unit, Milan, Italy; San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use*; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009503:Neutropenia / Q000139:chemically induced; D011788:Quality of Life; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D007155:Immunologic Factors; D013792:Thalidomide; D000077269:Lenalidomide