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1688 Multicenter Phase II Trial Addressing Lenalidomide Maintenance in Patients with Relapsed Diffuse Large B-Cell Lymphoma (rDLBCL) Who Are Not Eligible for Autologous Stem Cell Transplantation (ASCT): Efficacy and Safety Results after a Median Follow-up of Five Years

Program: Oral and Poster Abstracts
Session: 626. Aggressive Lymphoma (Diffuse Large B-Cell and Other Aggressive B-Cell Non-Hodgkin Lymphomas)—Results from Prospective Clinical Trials: Poster I
Hematology Disease Topics & Pathways:
Biological, Therapies, immunotherapy
Saturday, December 1, 2018, 6:15 PM-8:15 PM
Hall GH (San Diego Convention Center)

Andres JM Ferreri, MD1, Marianna Sassone, MD2*, Francesco Zaja, MD3*, Alessandro Re4*, Michele Spina, MD5, Alice Di Rocco6*, Alberto Fabbri, MD7*, Piera Angelillo, MD8*, Caterina Stelitano, MD9*, Maurizio Frezzato, MD10*, Chiara Rusconi11*, Renato Zambello, MD12*, Annalisa Arcari, MD13*, Giovanni Bertoldero, MD14*, Daniela De Lorenzo, BD1*, Eloise Scarano15*, Stefano Volpetti, MD16*, Salvatore Perrone, MD17*, Teresa Calimeri, MD PhD18, Caterina Cecchetti, MD19*, Fabio Ciceri, MD20* and Maurilio Ponzoni, MD 21

1Lymphoma Unit, Dept. of Onco-Hematology, IRCCS San Raffaele Scientific institute, Milano, Italy
2Lymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy
3S.C. Ematologia, Azienda Sanitaria Universitaria Integrata, Trieste, ITA
4Department of Hematology,, ASST Spedali Civili di Brescia, Brescia, ID, Italy
5Division of Medical Oncology, Nation Cancer Institute, Aviano, ITA
6Department of Cellular Biotechnologies and Hematology, Policlinico Umberto I, University "La Sapienza", Roma, Italy
7Department of Oncology, Division of Hematology, Azienda Ospedaliera Universitaria Senese, Siena, Italy
8Lymphoma Unit, Dept of Onco-Hematology, IRCCS San Raffaele Scientific Institute, MILANO, Italy
9Department of Haematology, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy
10Division of Hematology, San Bortolo Hospital, Vicenza, Italy
11ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
12Hematology and Clinical Immunology, Department of Medicine, Azienda Ospedaliera di Padova, Padova, Italy
13Hematology, Ospedale Guglielmo da Saliceto, Piacenza, Italy
14U.O. di Oncologia ed Ematologia Oncologica, Ospedale di Mirano, Mirano, Italy
15Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy
16Clinica Ematologica, Centro Trapianti e Terapie Cellulari “C. Melzi”, DAME, Università degli Studi, Udine, Italy
17Lymphoma Unit, Dept. fo Onco-Hematology, IRCCS San Raffaele Scientific Intsitute, Milano, Italy
18Lymphoma Unit, Dept of Onco-hematology, IRCCS San Raffaele Scientific Institute, Milano, Italy
19Lymphoma Unit, Dept of Onco-Hematology, IRCCS San Raffaele Scientific Institute, Milano, Italy
20Hematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milano, Italy
21Pathology Unit, IRCCS Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy

Background: Lenalidomide (LENA) maintenance is associated with significantly improved outcome in patients (pts) with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. Preliminary results of a multicentre phase II trial (NCT00799513), reported after a median follow-up of 25 months, showed a 1-yr PFS of 70 ± 7% and a 1-yr OS of 81 ± 6%, with good tolerability (Ferreri AJM, et al. Lancet Haematol 2017). However, LENA was ongoing in 41% of pts at time of analysis, and late side effects and events after maintenance completion remained to be defined. Herein, we report efficacy and safety results of the trial after a median follow-up of 56 (range 27-100) months.

Methods: HIV-neg pts (age ≥18 ys) with de novo or transformed DLBCL and relapsed disease responsive to conventional rituximab-containing salvage therapy were registered and treated with LENA 25 mg/day for 21 days out of 28, until lymphoma progression or unacceptable toxicity. A protocol amendment in 2015 allowed physicians to interrupt maintenance after a minimum duration of two years. Primary endpoint was 1-year PFS. Simon's two-stage optimal design was used. To demonstrate a 1-yr PFS improvement from 30% (P0) to 50% (P1), 47 pts (one-sided; α 5%; β 80%) were needed. Maintenance would be considered effective if ≥19 pts were progression-free survivors at 1 yr. Cell of origin was assessed by NanoString Technology (n=23) and Hans algorithm (n=39).

Results: Between 3/2009 and 12/2015, we recruited 48 pts; 46 of them were assessable (median age 72 ys; range 34-86); 36 pts had de novo DLBCL, 10 had transformed DLBCL. All pts were previously treated with anthracycline- and rituximab-based combination, plus ASCT in 6 pts. Thirty-three pts were enrolled at 1st relapse; salvage therapy contained high doses of cytarabine or ifosfamide in two-thirds of cases, and response was complete in 26 pts and partial in 20. Most pts had unfavourable features: IPI ≥2 in 38 (83%) pts, advanced stage in 35 (76%), extranodal disease in 29 (63%), high LDH level in 21 (46%); 28 (61%) pts were older than 70 ys.

Sixteen pts received ≥2 years of LENA (5 received >2 ys), 30 pts interrupted treatment due to progressive disease (PD; n= 17), toxicity (9) or pt refusal (4) (Table). LENA was well tolerated after an average of 18 courses/pt (range 3-82). With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Infections were rare, and well controlled with oral antibiotics (grade 1-2 in 9 courses; grade 3 in 3). LENA dose reduction was indicated in 25 pts (transient in 21), and was due to neutropenia (13), rash (7), diarrhoea (3), or neurotoxicity (2). Three (6%) pts died of toxicity during maintenance (intestinal infarction, meningitis and sudden death) and two pts died due to myelodysplastic syndrome (Table). Grade 4-5 toxicity and SAEs were equally distributed according to maintenance duration (Table).

At one year from trial registration, 31 pts were still progression free, which was significantly higher than the pre-determined efficacy threshold (n≥19). During the whole observation period, there were 24 events: progressive disease in 21 pts and death of toxicity in 3, with a 1-yr (primary endpoint) and 5-yr PFS of 67 ± 7% and 50 ± 7%, respectively. The duration of response to LENA was longer than response duration after the prior treatment line in 28 (61%) pts, and was twice as long in 21 (46%) of them. Twenty-six pts were disease-free at the last LENA course (Table), 22 of them remain relapse free after a median observation period from maintenance completion of 26 (8-92) months; 3 of the 4 relapses occurred in pts who received <1 yr of LENA (refusal or SAEs).

The benefit of LENA was observed both in pts with de novo or transformed DLBCL. According to the Hans’ algorithm, the 4-yr PFS was 50 ± 11% for GCB-DLBCL and 42 ± 11% for nonGCB-DLBCL (p= 0.58). Results using the Nanostring technique were consistent with the Hans’ algorithm. Overall, 28 (61%) pts are alive, with a 1- and 5-yr OS of 80 ± 6% and 60 ± 8%, respectively.

Conclusions: Long-term results of this trial soundly promotes the use of LENA maintenance in pts with chemosensitive relapse of DLBCL not eligible for ASCT or experiencing relapse after ASCT. LENA was well tolerated in this elderly population, without higher toxicity rates in pts treated for ≥2 years, and with enhanced survival figures. These results warrant further investigation of immunomodulatory drugs as maintenance in these high-risk pts.

Disclosures: Ferreri: Celgene: Research Funding. Zaja: Abbvie: Honoraria; Takeda: Honoraria; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria; Sandoz: Honoraria. Di Rocco: Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rusconi: Celgene: Research Funding.

*signifies non-member of ASH