Retrospective analysis on R‐DHAP/OX and ASCT as salvage treatment for relapsed/refractory high‐risk follicular lymphoma

The outcome of patients with follicular lymphoma (FL) experiencing disease progression within the first two years from first-line chemo-immunotherapy is poor and optimal subsequent management is uncertain. The combination of rituximab, dexamethasone, high-dose cytarabine, and cisplatin/oxaliplatin (R-DHAP/Ox) is active in germinal centerderived diffuse large B-cell lymphoma and is commonly used in FL prior to autologous stem cell transplantation (ASCT) in some Italian institutions. We identified all patients with FL that underwent R-DHAP/Ox at 3 institutions and retrospectively collected relevant clinical data. A total of 62 patients were identified, 46 of whom had relapsed within the first two years from the start of frontline chemo-immunotherapy, and 34 of whom underwent ASCT. The overall survival (OS) of patients relapsing in the first 2 years after chemo-immunotherapy was of 74.3% at 5 years (95% C.I. 61-87%), the median time to next treatment (TTNT) after R-DHAP/Ox was 30.9 months (95% C.I. 1874). Among patients that received ASCT the 5-year OS was 83.8% and the median TTNT was 38.5 months. Multivariate analysis of FLIPI at diagnosis, number of therapies prior to R-DHAP/Ox, response after first line and progression within 2 years from first line, did not demonstrate an association with OS for the considered variables. Prospective trials with R-DHAP/Ox +/ASCT in patients with FL relapsing within 2 years of frontline therapy are warranted. Introduction Data from the LymphoCare study demonstrated that patients with indolent follicular lymphoma that progresses within two years from the start of first-line chemoimmunotherapy with R-CHOP have a median overall survival (OS) of 5 years from the time of progression. These patients represent around 20% of all FL treated with first-line with chemo-immunotherapy, and for them optimal subsequent treatment remains uncertain. Second-line chemo-immunotherapy followed by consolidation with autologous stem cell transplantation (ASCT) has demonstrated significant activity in patients with previously treated FL. While selection of second-line therapy is frequently based on institutional standards, the combination of rituximab, dexamethasone, high-dose cytarabine, and cisplatin/oxaliplatin (R-DHAP/Ox) is an attractive option because it demonstrated superior outcomes to ifosfamide-based therapy in previously treated diffuse large B cell lymphoma with germinal center subtype, which shares the same cell of origin as FL. We hypothesized that the R-DHAP/Ox would be active therapy in patients with FL relapsing within the first two years following frontline chemoimmunotherapy and performed a retrospective study to evaluate the hypothesis. Methods The study was performed in accordance with IRB-approved protocols at each site (Universita' di Torino, San Bortolo Hospital, Citta' della Salute e della Scienza di Torino). All subjects had provided informed consent for the use of the clinical data. Patients were considered eligible if they had FL, if they had received at least one line of prior chemoimmunotherapy, and had received R-DHAP/Ox following disease progression. Subjects with histological transformation or grade 3B FL prior to receiving R-DHAP/Ox were excluded. Investigators recorded clinical data from electronic and paper medical records, including number and type of therapies before and after R-DHAP/Ox, response to R-DHAP/Ox and ASCT, main adverse events (infections requiring admission, inadequate stem cell collection, secondary malignancies, transformation to DLBCL), and survival outcomes. Response was estimated by investigators at each site based on standard International Working Group Criteria. Data of the patients were analyzed anonymously. OS was calculated from risk-defining events, as reported in the LymphoCare study, that is survival from the time of progression of disease (POD) for patients progressing in the first 2 years from first-line chemo-immunotherapy and from 2 years after diagnosis for the other group. Time to next therapy (TTNT) was calculated from the end of one line of therapy to start of the subsequent one. Survival probability was estimated with the Kaplan-Meyer method and difference between groups was tested by log-rank test. Cox proportional hazard regression was used to calculate hazard ratio and test the statistical significance. Median follow-up time was estimated by reverse Kaplan-Meier method. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). The primary objective was to describe the OS of patients that had experienced progressive disease within two years after first-line chemo-immunotherapy undergoing R-DHAP/Ox +/ASCT as salvage treatment. Secondary objectives were TTNT after RDHAP/Ox +/ASCT, and the association between fundamental clinical variables and OS. Results Patients A total of 67 patients, 42 men and 25 women, were identified; 62 met the eligibility criteria. Five patients were excluded: 2 progressed to DLBCL before starting RDHAP/Ox, 1 had grade 3b FL, 1 had a previous high grade lymphoma, 1 underwent chemotherapy in first line without anti-CD20 immunotherapy. Characteristics of the population at diagnosis are summarized in table 1. First line therapy First-line therapy was rituximab-cyclophosphamide-doxorubicin-vincristin-prednisone (R-CHOP) in 46 (74.2%), R-fludarabine-mitoxantrone in 5 (8%), rituximabcyclophosphamide-vincristine-prednisone (R-CVP) in 4 (6.4%), R-bendamustine in 2 (3.2%), rituximab-fludarabine-mitoxantrone-dexamethasone (R-FND) in 2 (3.2%), and 1 of each of R-chlorambucil, R-bendamustine-mitoxantrone and R-HDS (HD sequential of etoposide, cyclophosphamide, mitoxantrone, melphalan + ASCT). Rituximab maintenance after first-line was given to 13 patients (21%). Prior to R-DHAP/Ox, 45 (72.6%) underwent only 1 line of therapy, 14 (22.4%) underwent 2 lines of therapy, and 3 (5%) had 3 or more lines. Response to first-line chemo-immunotherapy was achieved in 92% (58% complete response [CR]); 5 patients (8%) reached only a stable disease (SD). The median TTNT from first-line was 22.1 months (95% C.I. 13.5 – 24.7), 48 patients progressed within the first two years (median TTNT 14.3 months [95% C.I. 10.6 – 19.4]). The characteristics of these early progressors relative to the population from the LymphoCare study are provided in Table 2. Overall response to last therapy prior to R-DHAP/Ox was 87.1% (CR 58%), 6.4% had a stable disease, and 4.8% were in progression of disease. For one patient (1.6%), assessment of response was not reported.