Treatment of Patients with Relapsed or Refractory Primary CNS Lymphoma (rrPCNSL) Enrolled in the Randomized Trials of the International Extranodal Lymphoma Study Group (IELSG)
Authors: Ferreri Andrés J M , Cwynarski Kate , Pulczynski Elisa , Fox Christopher P. , La Rosée Paul , Schorb Elisabeth , Krampera Mauro , Ilariucci Fiorella , Orsucci Lorella , Fabbri Alberto , Tucci Alessandra , Roeth Alexander , Linton Kim , Binder Mascha , Hemmaway Claire , Cabras Maria Giuseppina , Pinto Antonio , Calimeri Teresa , Cavalli Franco , Zucca Emanuele , Illerhaus Gerald 
Published: November 2021

Abstract
Background. Literature on the treatment of rrPCNSL is limited to a few retrospective studies and phase II trials addressing new drugs or strategies. Evidence supporting therapeutic choice in patients (pts) with rrPCNSL after modern high-dose-methotrexate (HD-MTX)-based chemotherapy (chemo) followed by consolidative whole-brain irradiation (WBRT) or autologous stem cell transplantation (ASCT) is lacking. We reviewed management and outcome of pts with rrPCNSL in the randomized trials of the IELSG, which included 294 assessable pts, treated with modern approaches, and followed for several years. Herein, we analyse efficacy of salvage options to provide recommendations for routine practice.
Methods. Pts enrolled in the IELSG20 or IELSG32 trials who experienced progressive disease (PD) at any time were considered. Pts who died due to toxicity and pts with extra-CNS relapse were excluded. Pts were grouped according to the time to progression after the first-line treatment: refractory (REF; relapse/PD ≤6 months from end of treatment), early relapse (ER; 6-35 months) and late relapse (LR; ≥36 months). Effect of salvage therapy on survival after relapse (SAR) was the primary objective. SAR was estimated from date of PD/relapse to date of death or last visit.
Results. 164 pts (median age 58, range: 26-70; 94 males) were considered: 119 (73%) REF, 24 (15%) ER and 21 (13%) LR. First-line chemo included HD-MTX in all pts, alone in 31, +cytarabine in 68, +cytarabine/rituximab in 36, and +cytarabine/rituximab/thiotepa (MATRIX regimen) in 29. Consolidation was part of first-line treatment in 58 (35%) pts: WBRT in 39 and carmustine-thiotepa/conditioned ASCT in 19; 106 pts did not receive consolidation due to PD during first-line chemo (n=96), pt refusal (2), poor conditions (4) or per protocol (4). Treatment of relapsed/PD was WBRT in 47 pts and chemo in 58; 59 pts received only supportive care (BSC) due to rapid neurological impairment or pt refusal. Importantly, except for performance status (ECOG PS 0-1: 49% of BSC pts, 70% of treated pts; p=0.009), pts managed with BSC showed the same characteristics (age, gender, extension of disease, first-line treatment) than pts who received salvage therapy. Salvage chemo consisted of HD-ifosfamide-based chemo (R-IE, RICE, DeVIC) in 20 pts, rechallenging with HD-MTX-based chemo (same regimen or ± other drugs) in 25, direct myeloablative chemo and ASCT in 3, single drugs in 10; 17 pts responsive to salvage chemo received consolidative ASCT (n=12) or WBRT.
Pts with LR had a better outcome than REF and ER cohorts, with a 2-year SAR of 64±11%, 11±3% and 13±7% (p= 0.001), respectively. These figures were similar when only treated pts were considered, with 2-year SAR of 80±11%, 17±4% and 23±12% (p= 0.0002), respectively. All untreated pts died of lymphoma within 4 months of progression. Salvage WBRT (n= 45) and chemo (n= 31) were associated with poor outcome in REF pts (2-year SAR 18±5% vs 16±6%; p= 0.76). Salvage treatment after ER or LR consisted of chemo in 27 pts and WBRT in two; HD-MTX retreatment showed a trend to a better outcome with respect to other chemo combinations, with a 2-year SAR of 73±12% and 27±13% (p=0.25), respectively. Importantly, 12 of the 15 pts with a SAR longer than one year were treated with HD-MTX-based chemo, followed by consolidation in 5 of them. A 2-year SAR of 90±9% was observed in the 11 LR pts retreated with HD-MTX-based chemo.
At a median follow-up from relapse/PD of 40 (range 3-118) months, 16 (10%) pts are alive and disease-free. Deaths were due to lymphoma in 137 (93%) pts, infections in six (4%), and thromboembolic events in two (1%); cause unknown in two pts. Multivariable analysis showed that ECOG PS 0-1, LR and HD-MTX retreatment were independently associated with better SAR and that outcome was not affected by age, gender, first-line induction and consolidation, and considered trial.
Conclusions. Mortality of rrPCNSL is regrettably high (≈90%), even among selected pts enrolled in prospective trials. One-third of pts are considered unsuitable candidates for salvage treatment. WBRT provides a marginal benefit over BSC in REF pts, suggesting that other strategies, including novel agents, should be considered in routine practice. Pts experiencing LR can achieve long-lasting second remission, especially when retreatment with HD-MTX-based chemo is feasible. Efficacy of salvage therapy appears to be independent of the first-line treatment.

Disclosures
Ferreri: Pfizer: Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Genmab: Research Funding; Amgen: Research Funding; Hutchison Medipharma: Research Funding; Beigene: Research Funding; BMS: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; PletixaPharm: Membership on an entity's Board of Directors or advisory committees; x Incyte: Membership on an entity's Board of Directors or advisory committees; Adienne: Membership on an entity's Board of Directors or advisory committees; Ospedale San Raffaele srl: Patents & Royalties. Cwynarski: Roche: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Takeda: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Celgene/BMS: Honoraria, Other: Travel / Conference Support; Atara: Honoraria; Gilead, KITE: Honoraria, Other: Travel / Conference Support, Speakers Bureau; Janssen: Honoraria, Other: Travel / Conference Support; Incyte: Honoraria, Speakers Bureau. Pulczynski: Roche: Research Funding. Fox: Abbvie: Honoraria, Research Funding; Astrazeneca: Honoraria; Atarabio: Honoraria; BMS/Celgene: Honoraria; Gilead: Honoraria, Research Funding; Janssen: Honoraria, Speakers Bureau; Incyte: Honoraria; Roche: Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Beigene: Honoraria, Research Funding. La Rosée: AstraZeneca: Honoraria; Bristol Myers Squib: Honoraria, Speakers Bureau; Novartis: Honoraria; Janssen-Cilag: Honoraria, Speakers Bureau; Abbvie: Honoraria, Speakers Bureau. Schorb: Roche: Research Funding; AbbVie: Research Funding; Riemser Pharma GmbH: Honoraria, Research Funding. Tucci: janssen: Membership on an entity's Board of Directors or advisory committees; Gentili: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Roeth: Roche: Consultancy, Honoraria, Research Funding; Kira: Consultancy, Honoraria; Bioverativ, a Sanofi company: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria. Linton: BeiGene: Research Funding; Celgene: Research Funding; University of Manchester: Current Employment; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hartley Taylor: Honoraria; Aptitude Health: Honoraria. Binder: Deutsche Krebsgellschaft, Medconcept GmbH, event Lab. GmbH: Honoraria, Other: Speaker Activity; Amgen GmbH, Janssen-Cilage GmbH, DGHO, Art tempi, Tumorzentrum Anhalt MD, Uniklinikum Hamburg, Sanofi Aventis: Honoraria, Other: Speaker Activity. Hemmaway: Abbvie: Honoraria. Pinto: Takeda: Consultancy; MSD: Honoraria; Bristol Myers Squibb-CELGENE: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau. Zucca: Celltrion Healthcare: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Miltenyi Biomedicine: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Gilead, Kite: Membership on an entity's Board of Directors or advisory committees; Abbvie: Other: Travel Support.