Lenalidomide in Combination with R-ESHAP (LR-ESHAP) in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Who Are Candidates for Autologous Stem-Cell Transplantation: A Phase 2 Study from the Spanish Group Geltamo

Background: Diffuse large B-cell lymphoma (DLBCL) patients with relapsed or refractory disease after rituximab-containing first-line therapy have poor outcomes with current salvage regimens. Accordingly, prospective studies incorporating new agents are needed for these patients. We conducted a phase 1b/2 trial to analyze the safety and efficacy of lenalidomide in combination with R-ESHAP (LR-ESHAP) in patients with relapsed or refractory DLBCL. The phase 1b part of the trial has been completed and lenalidomide 10 mg/day was identified as the maximum tolerated dose (MTD) (Martín et al, Br J Haematol 2016; 173: 245-52). Here we present the preliminary results of the phase 2 (ClinicalTrials.gov Identifier: NCT02340936).

Patients and methods: Eligible patients must be refractory to, or have relapsed following first-line treatment with rituximab in combination with an anthracycline-containing regimen and be eligible for autologous stem-cell transplantation (ASCT). Subjects received 3 cycles of lenalidomide 10 mg given on days 1 to 14 of every 21-day cycle, in combination with R-ESHAP salvage chemotherapy at standard doses (rituximab 375 mg/m² day 1, etoposide 40 mg/m² days 1-4, cisplatin 25 mg/m² days 1-4, cytarabine 2000 mg/m² day 5, and methylprednisolone 500 mg days 1-5). Responding patients received BEAM followed by ASCT. The primary endpoint was overall response rate (ORR) after 3 cycles of therapy. Secondary endpoints were complete remission (CR) rate, stem-cell mobilization activity, progression-free and overall survival, and toxicity.

Results:

Patient characteristics: 46 patients were included in the phase 2 analysis, of whom 12 were enrolled between January 2012 and March 2013, and had been given the MTD during phase 1; 34 were enrolled between January 2015 and November 2015. Median age was 58 (23-69) years, and 56.5% were male. Evaluable population per-protocol consisted of 44 patients because 2 patients were excluded during the first cycle due to withdrawal of consent and centralized diagnosis at relapse of lymphoblastic lymphoma, respectively. First-line treatment consisted of R-CHOP or similar in 38 patients, R-EPOCH in 3, VR-CAP in 1, and Burkitt lymphoma protocols in 2. Disease status at LR-ESHAP was: primary refractory disease in 67% of patients (partial response [PR] after first-line, n=13; and stable or progressive disease [<PR] after first-line, n=16), and relapsed disease in 33% (5 relapses occurred <1 year from diagnosis, and 10 late relapses). IPI was 0-1 in 38%, 2-3 in 48%, and 4-5 in 14%.

Feasibility and efficacy: 40 out of 44 patients (91%) received the planned 3 cycles of treatment (2 without lenalidomide in the third cycle due to toxicity) and 2 patients two cycles (due to persistent hematological and renal toxicities, respectively). Two patients discontinued treatment during the first cycle due to grade 3 infections (fungal pulmonary infection and mastoiditis, respectively). ORR to LR-ESHAP in the per-protocol population (n=44) was 68% (41% CR). Patients with relapsed disease had significantly better ORR and CR rates (87% and 67%, respectively) than patients in PR (77% and 31%) or <PR (37% and 25%) (p=0.004 and 0.02, respectively). Evaluation of response according to cell of origin (COO) is ongoing. Thirty-nine out of 42 patients (93%) were successfully mobilized after one (n=32) or two (n=7) mobilization procedures, and 28 (64%) underwent ASCT according to protocol, 1 of them after bone-marrow harvest. Reasons for not performing the transplant were: early progression (n=13), trial discontinuation due to toxicity (n=2), mobilization failure (n=1), and diagnosis of colon adenocarcinoma (n=1).

Toxicity: 42 serious adverse events (SAEs) have been reported during 128 cycles of treatment, including 14 episodes of febrile neutropenia (11%), 12 infections (9%), 2 renal disorders, 3 cardiac disorders, 3 thrombosis, and 8 other toxicities. All of them recovered except 1 case of colon adenocarcinoma in a patient with previous adenoma in the same location. There were no treatment-related deaths during LR-ESHAP cycles.

Conclusions: LR-ESHAP is safe, feasible and associated with high response rates in rituximab-pretreated relapsed or refractory DLBCL patients. Longer follow-up is needed to perform survival analysis. Efficacy analysis according to COO is ongoing.