scholarly journals Efficacy of High Dose Chemotherapy with Autologous Transplantation for Primary CNS Lymphoma Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 3-4
Author(s):  
Muhammad Khawar Sana ◽  
Syed Maaz Abdullah ◽  
Muhammad Tayyeb ◽  
Mohammad Ammad Ud Din ◽  
Amrat Ehsan ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adverse Effects ◽  
Autologous Transplantation ◽  
Primary Cns Lymphoma ◽  
High Dose Chemotherapy ◽  
Cns Lymphoma ◽  
High Dose ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Related Mortality

Introduction: Primary CNS lymphoma (PCNSL) is a highly aggressive non-Hodgkin lymphoma (NHL) variant limited to the CNS with rare evidence of systemic spread. It constitutes 4% of all CNS malignancies. Owing to the impenetrable blood-brain barrier to routine chemo-immunotherapy, the efficacy of such treatment is less than optimal. The combination of chemoradiotherapy has substantial associated risk of late neurotoxicity and increased disease recurrence. High dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) as rescue has been shown to be effective. We performed a systematic review of literature to explore the efficacy of HDT and ASCT in patients with PCNSL. Methods: We performed a comprehensive literature search (following PRISMA guidelines) on May 28, 2020 on Pubmed, Cochrane Library and Clinicaltrials.Gov by using the MeSH terms related to high-dose chemotherapy, autologous transplantation and primary CNS lymphoma which yielded 561 relevant articles. Following subsequent screening by 2 reviewers, we selected 16 published trials (n=745) and included data from these studies in our systematic review. We manually extracted data summarized the results. Results: 405/745 patients eventually underwent sequential HDT+ASCT the results of which are illustrated in table 1 and 2 stratified on the basis of newly diagnosed (ND) (n=641) and relapsed, refractory (RR) PCNSL patients (n=104) respectively. ND PCNSL: Among ND PCNSL patients, carmustine and thiotepa based regimens were the most widely studied HDT regimens (n= 351). Illerhaus et al. (2016, n= 81) in a phase 2 trial used HDT of intravenous (IV) combinations of rituximab, thiotepa and carmustine followed by ASCT on 73 patients which yielded partial response (PR) 13.9 %, complete response (CR) 77.2% and overall survival (OS) 81% at 36 months. 4 patients suffered transplant related mortality (TRM), mucositis (8%) and arrhythmias (2%) were the most common nonhematologic >grade 4 adverse effects. Ferreri et al. (2017) [n=122] in a phase 2 trial (n=59) used ASCT following Carmustine + Thiotepa HDT and reported 2-year OS of 71% and CR of 93% with a modest toxicity profile (infections (8%), mucositis (5%) and 2 (3%) treatment related deaths). IV thiotepa, busulfan and cyclophosphamide (TBC) combination was used as HDT / ASCT in ND PCNSL patients (n=208). Omuro et al. (2015) (n=32) used HDT with TBC followed by ASCT in 26 patients. Whole brain radiation therapy (WBRT) was not given to any patient regardless of recurrence or relapse. At 5 years, the study reported PR=11%, CR=81%, and OS=81%. In a phase 2 trial, Houillier et al. (2019, n=140) used TBC combination as HDT followed by either WBRT or ASCT (2 separate arms), 44 patients of the latter arm exhibited a CR of 38% and OS of 66% at 5 years with 5 treatment related deaths. An IV combinations of carmustine, etoposide, cytarabine and melphalan (BEAM) have also been used as HDT with ASCT in 3 phase 2 trials (n=59). Abrey et al. (2003, n=28) in a phase 2 trial used high-dose BEAM therapy followed by ASCT which yielded PR of 14%, CR of 57% and OS of 55% at 28 months. Only 1 treatment related mortality occurred. RR PCNSL: TBC combination has been the most extensively used HDT regimen for RR PCNSL patients undergoing ASCT (n=65). Soussain et al. (2008, n=43) conducted a phase 2 trial in which high-dose TBC sequentially followed by ASCT was studied in 27 RR PCNSL patients. The results showed median PFS of 41.1 months with OS of 45% at 2 years however, 3 toxicity related deaths were observed. Kasenda et al. (2017, n=39) in a phase 2 trial used high-dose combination of rituximab, carmustine and thiotepa coupled with ASCT on RR PCNSL patients which yielded PR of 15.4%, CR of 56% and median PFS of 12.4 months with an OS of 56.4% at 2 years. However, there were 4 treatment related deaths and an extensive toxicity spectrum with widespread pancytopenia (thrombocytopenia =96.9%, leukopenia =100%, anemia =65.6%) and nonhematologic infections (65.6%) observed. Conclusion: HDT followed by ASCT rescue has exhibited favorable outcomes and can be used an alternative to WBRT especially in ND PCNSL patients. Evidence is limited by mainly phase II non randomized data. Although, hematologic adverse effects due to HDT were observed on a widespread basis, transplant related mortality was however minimal. There is need to carry out prospective randomized phase III trials to access the safety and efficacy profile of HDT / ASCT for ND and RR PCNSL. Table Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

A Systematic Review of High Dose Chemotherapy with Autologous Transplantation in Secondary CNS Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 14-14
Author(s):  
Syed Maaz Abdullah ◽  
Sikander Abdullah ◽  
Muhammad Khawar Sana ◽  
Hamid Ehsan ◽  
Syeda Aiman Gohar Naqvi ◽  
...  
Keyword(s):  
Systematic Review ◽  
High Dose Chemotherapy ◽  
Cns Lymphoma ◽  
High Dose ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Whole Brain Radiation ◽  
Phase 2 Trial ◽  
Brain Radiation

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.

High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: a randomised phase 2 trial

The Lancet ◽  
2009 ◽  
Vol 374 (9700) ◽  
pp. 1512-1520 ◽  
Author(s):  
Andrés JM Ferreri ◽  
Michele Reni ◽  
Marco Foppoli ◽  
Maurizio Martelli ◽  
Gerasimus A Pangalis ◽  
...  
Keyword(s):  
Primary Cns Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
Dose Methotrexate ◽  
High Dose Cytarabine

scholarly journals Improving the antitumor activity of R-CHOP with NGR-hTNF in primary CNS lymphoma: final results of a phase 2 trial

2020 ◽  
Vol 4 (15) ◽  
pp. 3648-3658
Author(s):  
Andrés J. M. Ferreri ◽  
Teresa Calimeri ◽  
Maurilio Ponzoni ◽  
Flavio Curnis ◽  
Gian Marco Conte ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Primary Cns Lymphoma ◽  
Human Tumor ◽  
Central Nervous System Lymphoma ◽  
B Cell Lymphoma ◽  
Cns Lymphoma ◽  
High Dose ◽  
Phase 2 ◽  
Phase 2 Trial

Abstract Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment of diffuse large B-cell lymphoma (DLBCL). Primary DLBCL of the central nervous system (CNS) (primary central nervous system lymphoma [PCNSL]) is an exception because of the low CNS bioavailability of related drugs. NGR–human tumor necrosis factor (NGR-hTNF) targets CD13+ vessels, enhances vascular permeability and CNS access of anticancer drugs, and provides the rationale for the treatment of PCNSL with R-CHOP. Herein, we report activity and safety of R-CHOP preceded by NGR-hTNF in patients with PCNSL relapsed/refractory to high-dose methotrexate-based chemotherapy enrolled in a phase 2 trial. Overall response rate (ORR) was the primary endpoint. A sample size of 28 patients was considered necessary to demonstrate improvement from 30% to 50% ORR. NGR-hTNF/R-CHOP would be declared active if ≥12 responses were recorded. Treatment was well tolerated; there were no cases of unexpected toxicities, dose reductions or interruptions. NGR-hTNF/R-CHOP was active, with confirmed tumor response in 21 patients (75%; 95% confidence interval, 59%-91%), which was complete in 11. Seventeen of the 21 patients with response to treatment received consolidation (ASCT, WBRT, and/or lenalidomide maintenance). At a median follow-up of 21 (range, 14-31) months, 5 patients remained relapse-free and 6 were alive. The activity of NGR-hTNF/R-CHOP is in line with the expression of CD13 in both pericytes and endothelial cells of tumor vessels. High plasma levels of chromogranin A, an NGR-hTNF inhibitor, were associated with proton pump inhibitor use and a lower remission rate, suggesting that these drugs should be avoided during TNF-based therapy. Further research on this innovative approach to CNS lymphomas is warranted. The trial was registered as EudraCT: 2014-001532-11.

scholarly journals SS-4 High dose chemotherapy with autologous hematopoietic stem cell transplantation for CNS lymphoma

2020 ◽  
Vol 2 (Supplement_3) ◽  
pp. ii2-ii2
Author(s):  
Eisei Kondo
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Primary Cns Lymphoma ◽  
High Dose Chemotherapy ◽  
Cns Lymphoma ◽  
High Dose ◽  
Hematopoietic Stem

Abstract High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HDT-ASCT) is listed as a consolidation therapy option for primary central nervous system (CNS) lymphoma in the guidelines of western countries. The advantages of HDT-ASCT for primary CNS lymphoma as consolidation are believed to be high rates of long-term remission and lower neurotoxicity, even though its eligibility is limited to younger fit patients. In the Japanese guideline, HDT-ASCT for primary CNS lymphoma is however not recommended in daily practice, mainly because thiotepa was unavailable since 2011. The Japanese registry data for hematopoietic transplantation have shown that primary CNS lymphoma patients were treated with various HDT regimens and thiotepa-containing HDT was associated with better progression free survival (P=.019), lower relapse (P=.042) and a trend toward a survival benefit (Kondo E et al, Biol Blood Marrow Transplant 2019). A pharmacokinetic study of thiotepa(DSP-1958) in HDT-ASCT for lymphoma was conducted in 2017, and thiotepa was approved for HDT-ASCT in lymphoma this March, meaning that optimal HDT regimen for CNS lymphoma is now available in Japan. The treatment strategy of CNS lymphoma needs further development to improve survival and reduce toxicity.

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