Novel Combination Of Lenalidomide-Rituximab Provides An Effective Bridge To Stem Cell Transplantation In Relapsed and/Or Refractory Aggressive B-Cell Non-Hodgkin’s Lymphomas: A Single Center Experience

Chemosensitive disease before stem cell transplantation (SCT) has been considered as one of the most important prognostic factors in predicting favorable outcomes following SCT. However, chemotherapy resistance develops rapidly in relapsed and/or refractory aggressive B-cell non-Hodgkin’s lymphomas (NHL). Development of novel target drugs and regimens may help address these clinical issues. Our phase I/II clinical trial confirms that lenalidomide plus rituximab (LR) is well tolerated and effective for patients with relapsed and/or refractory B-cell NHL.

We retrospectively analyzed the data from our clinical trials of LR in aggressive NHL patients [Mantle Cell Lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular grade 3 lymphoma (FLG3) and transformed large cell lymphoma (TL)](Wang et al., Lancet Oncol 13:716-23, 2012; Wang et al., Leukemia 2013 Apr 2) and provided further details and longer follow-up on the efficacy and safety of novel combination of LR followed by SCT. Patients enrolled in our clinical trials received oral lenalidomide 20 mg once daily on days 1-21 of each 28-day cycle and 375mg/m² of intravenous rituximab once a week for four weeks only during cycle one, beginning on day 1. Patients were treated with LR until disease progression, SCT, or withdrawal due to toxicity. Overall survival (OS) was defined as time from study entry to the date of death or until the last survival date if still alive. Progression-free survival (PFS) was defined as time from study entry to the date of disease progression or death.

From March 31, 2006 to December 15, 2010, twenty-two patients were enrolled in our study and underwent SCT after receiving LR combination. Patients received either allogeneic (n=16) or autologous (n=6) SCT following the study treatment. The median age of the patients was 59.5 years (range, 46-74), and 18 of them were male. The median time from diagnosis to initiation of LR therapy was 25.5 months (range, 3-99.4). The median number of previous treatment regimens was two (range, 1-4). Five (23%) patients received SCT before enrolling in our study. All patients had received previous rituximab-containing treatments. Histologies were: MCL (n=12), DLBCL (n=5), FLG3 (n=1) and TL (n=4). Of the sixteen patients who proceeded to allogeneic SCT, two were given myeloablative conditioning regimens, the remaining fourteen were given the reduced intensity conditioning (RIC) regimens. The preparative regimens were FCR(fludarabine + cyclophosphamide + rituximab) in 2 patients, FCR plus alemtuzumab in 2, or plus alemtuzumab and low dose TBI(total body irradiation) in 3, or plus Ibritumomab Tiuxetan(zevalin) in 3, fludarabine+bendamustine/ rituximab in 2, fludarabine+ busulfan in 1 and others in 3. All of the six patients who proceeded to auto-SCT were given R-BEAM( rituximab, BCNU, etoposide, cytarabine, melphalan) regimen. Eleven patients underwent SCT from a matched unrelated donor and five from a matched sibling donor. The median time from best response date of LR regimen to SCT date was 4 months (range 1-14).

The ORRs were 77% (n=17, with 10 CR + 7 PR) before undergoing SCT and 100% (n=22, all of patients got CR) following SCT. Hematological toxicity of LR combination was common. Grade 3-4 hematological toxicities included neutropenia (87%), lymphopenia (46%) and thrombocytopenia (41%). Eight (36%) patients required dose reductions and neutropenia was the most frequent cause. Incidence of acute graft versus host disease (GVHD) (grade II-IV) and chronic GVHD following SCT were: 31% (5/16) and 56% (9/16), respectively.

After a median follow-up of 22 months (range 6-59), nine (41%) patients were alive [MCL(n=2), DLBCL(n=3), TL(n=3), FLG3(n=1)]. Two (9%) patients who received auto-SCT died due to progression of disease (one with MCL and another with DLBCL ), ten (45%) due to complications following a subsequent allogeneic transplant (GVHD, pneumonia and sepsis), and one (4.5%) due to liver failure following auto-SCT. The median PFS was 21 months. Estimated 1-year, 3-year and 5-year PFS rates were 77.3%, 30.3% and 30.3%, respectively. Median OS times were 30 months. Estimated 1-year, 3-year and 5-year OS rates were 95.5%, 38.6% and 38.6%, respectively.

The results suggest that the novel combination of LR is an effective and safe regimen, and may offer a bridge to SCT in patients with relapsed and/or refractory aggressive B-cell NHL.

No relevant conflicts of interest to declare.