Lenalidomide and Rituximab (ReRi) As Front-Line Chemo-Free Therapy for Elderly Frail Patients with Diffuse Large B-Cell Lymphoma. a Phase II Study of the Fondazione Italiana Linfomi (FIL)

Abstract

INTRODUCTION Treatment of Diffuse Large B cell lymphoma (DLBCL) in the elderly population is challenging as many patients (pts) are not eligible to receive standard curative therapy, due to comorbid conditions and to a higher susceptibility to the side effects of standard anthracycline containing regimens. Among currently available active drugs, Lenalidomide has been used in the setting of relapsed/refractory DLBCL both as monotherapy and in combination with rituximab, showing a good activity and an acceptable safety profile. We started a prospective, multicenter, single arm, phase II trial to demonstrate activity and safety of a chemo-free combination of lenalidomide + rituximab in older (≥ 70 years) untreated pts with DLBCL who were prospectively defined as frail according to the simplified comprehensive geriatric assessment (sCGA) (Tucci A. et al., Leuk Lymphoma. 2015 Apr). PATIENTS AND METHODS Pts were eligible if they were previously untreated DLBCL patients, older than 69 years and defined as frail according to sCGA. The treatment consisted of a 28-day cycle (R2) combining oral Lenalidomide (20 mg on days 1 to 21) and i.v. Rituximab (375 mg/m2 on day 1); a maximum number of 6 cycles was planned; response assessment was performed after cycles 4 and 6. At the end of the 6 th cycle, patients with partial or complete response continued treatment with Lenalidomide 10mg/d on days 1 to 21 every 28 days, until cycle 12or unacceptable toxicity. Final response was evaluated within 28 days after the last study drug administration. Primary study endpoint was Overall Response Rate (ORR) after 6 R2 cycles, defined according to Lugano 2014 criteria; co-primary endpoint was the rate of extra-hematological toxicity with CTCAE grade >2 and of death for any cause during the treatment The study was planned according to a two stage Simon design. A total of 68 pts had to be enrolled to complete the study. With 34 responses the study would be able to demonstrate the initial hypothesis of an improvement of response rate from 45% (p0) to 65% (P1) RESULTS From August 2018 to June 2021, 68 newly diagnosed frail DLBCL were enrolled in 18 Italian centers. Median age was 83 years (range 70-91) and 73% had stage III/IV; 57% had High risk IPI (i.e. 3-5 risk factors). 64 pts were confirmed eligible and started R2 treatment. The planned 6 courses of R2 were completed in 36 pts (56%). The median number of R2 cycles was 6 (1-6). Treatment was discontinued in 28 pts due to lymphoma progression (11 cases), extra-hematological toxicity (7), hematological toxicity (1), lost after 1 cycle and investigator choice after 5 cycles in CR in 1 case each, death in 7 cases (1 each for infection, pancytopenia, cachexia, ischemia and bowel infarction, and from unknown causes in 2 cases). At the end of 6 th R2 cycle 26 patients achieved a response (ORR 41%), 13 CR and 13 PR. After a median follow-up of 17 months, the overall survival, and progression free survival at 12 months were 69% (95CI 56-79%) and 55% (95%CI 42-66%), respectively. The duration of remission at 12 months was 72%. Regarding safety 46 events were reported including 31 extra-hematological toxicities > CTCAE grade 2: 7 cardio-vascular (1 resulting in death), 4 nervous system disorders (1 resulting in death), 10 gastro-intestinal, 3 infections, 6 skin and subcutaneous tissue disorders, 5 respiratory events (all resolved). The rate of grade 3-4 adverse events was higher than the highest allowed limit of 28. CONCLUSIONS The Reri is the first study to evaluate activity and safety of a chemo-free therapy in patients with diffuse large B-Cell Lymphoma who are not eligible for conventional cytotoxic therapy. Even if this study was not able confirm the initial activity hypothesis, activity of the R2 combination was observed in a significant proportion of cases warranting further exploration of chemo-free approach of elderly frail patient with DLBCL. Disclosures Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Fabbri: Takeda: Honoraria; Servier/Pfizer: Honoraria; Takeda: Other: Travel, Accomodations, Expenses. Musuraca: janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau; Roche, Italfarmaco: Consultancy, Honoraria; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations. Luminari: Roche, Celgene, Teva Pharmaceuticals, Gilead Sciences, and Takeda Pharmaceuticals: Honoraria.

Remarkable Remission Rate and Long-Term Efficacy of Upfront Metronomic Chemotherapy in Elderly and Frail Patients, with Diffuse Large B-Cell Lymphoma

“…In fact, following R-miniCHOP the 24-months disease free survival was reported to be slightly less than 60% (vs. 74% for R-DEVEC) [ 5 ]. Furthermore, two recent trials based on Rituximab-lenalidomide [ 11 ] and Rituximab-lenalidomide-ibrutinib(iR2) [ 12 ] combinations, respectively, reported a 12-months PFS of 55%, [ 11 ] and a 24-months PFS of 53%, respectively. We acknowledge these comparisons, although intriguing, remain speculative.…”

“…Conversely, ongoing clinical trials based on immunomodulators [ 8 ], new monoclonal antibodies [ 9 ] and small molecules targeting pathogenetic pathways [ 10 ] will hopefully help a shift towards therapeutic schedules defined as chemo-free, in vulnerable DLBCL. As a matter of fact, results from a few phase II trials, based on chemo-free combinations, have already reported encouraging data [ 11 , 12 ].…”

Lenalidomide plus R-GDP (R2-GDP) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Final Results of the R2-GDP-GOTEL Trial and Immune Biomarker Subanalysis

“…The most common G3–4 AEs were thrombocytopenia (60.2%), neutropenia (60.2%), anemia (26.9%), asthenia (19.2%), infection (15.3%), and febrile neutropenia (14.1%), with 4 (5.1%) toxic deaths (G5 febrile neutropenia with associated septic shock) as expected from the common toxicity with the use of lenalidomide schedules ( 7, 25, 26 ). Chemo-free therapies with R2 combination (rituximab–lenalidomide 20 mg D1–21) used by Wang and colleagues ( 26 ) in R/R DLBCL and by Gini and colleagues ( 25 ) in front-line DLBCL showed common G3–4 AEs, including neutropenia (52%), thrombocytopenia (36%), anemia (20%), and febrile neutropenia (11%; ref. 26 ), with 4 (5.9%) deaths (2 patients due to visceral arterial ischemia and 2 due to infectious disease; ref.…”

“… 26 ), with 4 (5.9%) deaths (2 patients due to visceral arterial ischemia and 2 due to infectious disease; ref. 25 ). R2-chemotherapy (CHOP) schedule with lenalidomide 15 mg D1–14 of every 21-day cycle, used by Nowakowski and colleagues ( 7 ) in the phase III ROBUST study with previously untreated patients with ABC-type DLBCL describes neutropenia (60%), anemia (22%), thrombocytopenia (17%), and febrile neutropenia (14%) as most common G3–4 AEs, and 3 deaths due to AEs (not otherwise specified), so lenalidomide dose adjustments were planned to manage toxicity.…”

R-CEOP as first-line treatment for anthracycline-ineligible patients with diffuse large B-cell lymphoma

“…Non-pegylated liposomal doxorubicin has been assessed in patients diagnosed with DLBCL, with no difference observed in cardiotoxicity [7,8]. In combination with rituximab, anthracyclinefree regimens include cyclophosphamide, vincristine and prednisone (R-COP), gemcitabine and oxaliplatin (R-GemOx), lenalidomide (R2), bendamustine, gemcitabine, cyclophosphamide, vincristine, and prednisolone (R-GCVP) [9][10][11][12]. And while these regimens are generally well tolerated showing 2-year OS ranging from 38 to 65%, these are considered palliative options.…”