Ehsan, Hamid

Introduction: Secondary Central Nervous System Lymphoma (SCNSL) is the spread of a lymphoma to the CNS, the primary focus of which is situated elsewhere in the body. Most commonly, it is a non-Hodgkin lymphoma which either presents as a CNS involvement due to systemic relapse or progression, or as an isolated relapse in the CNS despite systemic remission. Traditionally, it has been treated by intrathecal or systemic chemotherapy and/or WBRT (Whole-brain radiation therapy) but recently, the use of high-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has shown encouraging results. We present a systematic review of literature displaying the treatment outcomes of HDT/ASCT in SCNSL. Methods: We performed a comprehensive literature search (following PRISMA guidelines) on July 08 2020 on PubMed, Cochrane Library and Clinicaltrials.Gov by using the relevant MeSH terms of high-dose chemotherapy, autologous stem cell transplantation, CNS lymphoma, efficacy and safety. Following screening by 2 reviewers, we selected 12 published studies (n=353) and included data from these studies in our systematic review. We manually extracted data summarized the results. Results: 232/353 patients eventually underwent sequential HDT+ASCT who were evaluable for treatment response out of which 190 patients had SCNSL (see table 1). Carmustine (BCNU) based HDT: BCNU based regimens have been the most extensively studied HDT among SCNSL patients (n=81). Korfel et al. in a phase 2 trial (2013, n=30) used HDT combination of BCNU, thiotepa and etoposide followed by ASCT in SCNSL patients. No patient was given whole brain radiation therapy (WBRT). The results yielded a PR of 8%, CR of 63% and 2-year OS of 63%. 1 toxicity related mortality (TRM) was noted and >grade 4 adverse effects included infection (4%) and stomatitis (13%). Ferreri et al. (2015, n=38) in a phase 2 trial use HDT with BCNU plus thiotepa on 38 patients 20 of whom underwent subsequent ASCT. The results showed CR of 100%, event free survival (EFS) of 40% ±9% and OS of 41% ±8% at 5 years with four patients suffering TRM. Thiotepa, busulfan and cyclophosphamide (TBC) based HDT: The combination based on TBC has been a popular option for SCNSL patients (n=53). In a retrospective analysis by Welch et al. (2014, n=17), TBC combination followed by sequential ASCT was studied in both primary and SCNSL patients (primary malignancy being diffuse large B-cell lymphoma) and the collective results showed complete response (CR) of 100%, PFS of 93% (95% CI: 61-99%) and OS of 93% (95% CI: 61-99%) at 3 years. In addition to the excellent efficacy response, no TRM or grade 4 toxicities were documented. Chen et al. (2015, n=12) in a phase 2 trial used HDT with rituximab and TBC (R-TBC) combination followed by ASCT rescue in 12 SCNSL patients. At 2 years, the progression free survival (PFS) was 51% (95% CI: 18-77%) and overall survival (OS) was 83% (95% CI: 48-96%). Two patients developed neurotoxicity and one TRM was recorded. Methotrexate (MTX) based HDT: MTX based combinations have also been widely used as HDT preceding ASCT in SCNSL patients (n=51). Fischer et al. (2008, n=20) studied HDT of MTX plus ifosfamide (IFO) in a retrospective analysis which showed PR of 30%, CR of 60% and median OS of 8.7 months and two TRM (due to sepsis in neutropenia) in SCNSL patients. Lee et al. (2015, n=31) in a prospective cohort study evaluated HDT with MTX based multidrug combination with ASCT in SCNSL patients which yielded a PR of 41.6%, CR of 50% and OS of 9 months (95% CI: 5-12 months). Five patients had suffered TRM. Conclusion: The combination of HDT with ASCT has yielded promising treatment outcomes both in terms of favorable efficacy rates and reduced rates of toxicity in SCNSL patients proving to be a comparable alternative to traditionally used chemo-radiation. However, the data at present is limited to few phase 2 trials with some being displayed collectively with data of primary CNS lymphoma patients. There is an increased need to carry out randomized phase 3 trials exclusively on SCNSL patients to better predict the efficacy and safety profile of HDT/ASCT in these patients. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Introduction: According to the National Comprehensive Cancer Network (NCCN) 2019 guidelines on multiple myeloma (MM) treatment, three-drug regimens using bortezomib (V) and dexamethasone (d) in combination with either lenalidomide (R), (VRd) or Cyclophosphamide (C) combination (VCd) are standard first-line treatment options in newly diagnosed multiple myeloma (NDMM), regardless of transplant eligibility. However, the two combinations have not been studied head-to-head. This systemic review aims to compare the efficacy and safety outcomes of VCd versus VRd in NDMM patients. Methods: We performed a comprehensive literature search on PubMed, Cochrane Library, and ClinicalTrials.gov on July 27, 2020. We used the MeSH terms for 'multiple myeloma', 'cyclophosphamide', 'bortezomib', 'dexamethasone', 'lenalidomide', and their associated keywords. The search yielded 410 articles. Screening and data extraction were done according to PRISMA guidelines. After excluding case reports, case series, observational studies, review articles, meta-analysis, and retrospective studies, 11 phase II and III clinical trials (n=1088) were included of which three assessed VCd and eight assessed VRd in NDMM. Results: There was no trial on the direct comparison of VCd with VRd. Total 111 NDMM patients were evaluable who received VCd (Table 1). Moreover, total 977 NDMM patients were evaluable who received VRd (Table 2). VCd arm results: Reeder et al. (2009, n=33) achieved the best ORR of 88% which was largely VGPR or better (61%). Tuchman et al. (2017, n=14) reported similar results of ORR (64%) with 58% achieving VGPR or better and 7% achieving PR. Contrary to these ORR distributions, Sunami et al. (2019, n=64) reported the ORR of 80% which was largely driven by PR of 41%. Moreover, a 2-year OS of 97% and PFS of 77% which is consistent with previous results. The toxicity profile with VCd was manageable with mostly hematological adverse events. Neuropathy was significantly lower when compared to VRd. VRd arm results: NDMM patients, in a phase III trial by Durie et al. (2016, n=471) achieved ORR of 82% (PR=38%, VGPR=28%, and CR=16%) with VRd. The mPFS was 43 months and mOS was 75 months, both significantly better than control. Stadtmauer et al. (2019, n=254) results were similar as well with 3-year PFS and OS as 58% and 85% respectively. Kumar et al. (2012, n=42) had a 1-year OS of 100% and PFS of 83%. O'Donnel et al. (2018, n=50) achieved mPFS of 35 months while mOS could not be reached. Luoma et al. (2019, n=78) achieved a 3-year PFS of 52% while OS of 83%. Severe neuropathy was reported with VRd regimen. The remaining toxicity profile was mostly hematological and manageable with prompt intervention. Conclusion: The two upfront regimens of VCd and VRd show favorable efficacy and safety outcomes in NDMM patients. VRd arm achieves relatively higher rates of ORR, CR and VGPR. Cost-effectiveness and lower neuropathy incidence associated with VCd makes it favorable over VRd. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.