Outcomes of Patients with Primary Central Nervous System Lymphoma Treated with Matrix Followed By High-Dose Chemotherapy and Autologous Stem Cell Transplant - a Multicentre, Retrospective Study

Background:

Methotrexate, cytarabine, thiotepa and rituximab (MATRix) followed by high-dose chemotherapy (HDC) with a thiotepa-containing regimen and autologous stem cell transplant (ASCT) has become standard in Canadian centers for treatment of primary central nervous system lymphoma (PCNSL). However, there remains variation in high-dose chemotherapy regimens used, including thiotepa dosing. In Ontario, Canada's most populous province, patients at Princess Margaret Cancer Centre (PM) until 2021 underwent conditioning with carmustine and thiotepa 10mg/kg divided over 2 days. In December 2021, the thiotepa dose in the conditioning regimen was increased to 20mg/kg divided over 2 days aligning with the IELSG32 trial. At Juravinski Hospital (JH), patients are treated with busulfan (9.6mg/kg over 3 days) and thiotepa 600mg/m² over 2 days. In a 70kg patient, with 1.9m² BSA this would result in a 50% reduced dose of thiotepa at PM prior to December 2021, and a 17% reduced dose of thiotepa if treated at JH, compared to PM from December 2021 onwards (the IELSG32 dosing).

Aim:

As it is not clear if differences in thiotepa dosing impact clinical outcomes, we aimed to assess overall survival (OS), progression-free survival (PFS) and transplant toxicities of patients treated with MATRix followed by three different HDC regimens and ASCT at 2 large transplant centres in Ontario, Canada.

Methods:

We performed a retrospective review of patients with PCNSL treated with MATRix followed by HDCT and ASCT from 2017-2022 at PM, and from 2017-2020 at JH. Patients were included if they were >18 years, treated with MATRix first-line or for relapsed/refractory disease, and underwent consolidation with ASCT. Data on stem cell collection, conditioning regimen, and transplant toxicities were collected. OS and PFS were calculated using Kaplan-Meier method, and Cox regression analysis was used to assess the impact of patient and treatment variables on outcomes.

Results:

At PM and JH, 52 patients were treated with MATRix followed by HDC and ASCT and were included: 18 at JH with busulfan and thiotepa 600mg/m² over 2 days (Cohort 1), 23 at PM with carmustine and thiotepa 10mg/kg over 2 days (Cohort 2), and 11 at PMCC with carmustine and thiotepa 20mg/kg over 2 days (Cohort 3). Patients were followed for a median of 26 months, 41 months and 15 months, respectively. There were no differences between cohorts in age or use of MATRix as first-line therapy. Most patients achieved a complete response (CR) or partial response (PR) on pre-ASCT MRI (83% in cohort 1, 87% in cohort 2, 100% in cohort 3, p=0.592). One patient in cohort 1 and 1 in cohort 2 had progressive disease after MATRix requiring salvage chemotherapy prior to ASCT.

The median number of CD34+ cells infused per kg was 4.7 in cohort 1, 3.45 in cohort 2, 6.04 in cohort 3, p=0.036. Patients in cohorts 1 and 3 had higher rates of febrile neutropenia compared to patients in cohort 2 (94.4% and 81.8% compared to 65.2%, p=0.014). Median days to neutrophil recovery and platelet count recovery were similar (p=0.292 and 0.226 respectively). CR after ASCT was achieved in 13/18 patients (72%) in cohort 1, 13/23 patients (57%) in cohort 2 and 8/11 patients (73%) in cohort 3, p=0.288.

The 18-month OS was 94.4% in cohort 1, 94.7% in cohort 2 and 90.9% in cohort 3 (p=0.545). The 18-month PFS was 94.1% in cohort 1, 86.3% in cohort 2, and 90.0% in cohort 3 (p=0.790). Over a median follow up of 26 months (range 1-79), there were 8 deaths. Causes of death included progression of lymphoma in 5 patients, infectious complications in 2 (pneumocystis pneumonia and bacterial sepsis), and an unrelated cause in 1 patient. Results from a Cox proportional hazard model showed no impact of baseline demographic features (age, sex, CD34+ cell dose collected), or treatment-related factors (conditioning regimen, achieving CR prior to ASCT, achieving CR after ASCT) on OS or PFS.

Conclusion:

These data from 2 academic transplant centres shows outcomes with MATRix followed by HDC with a thiotepa-based regimen and ASCT for patients with PCNSL are encouraging. Acknowledging the limited sample size and non-randomized comparison, differences in conditioning regimens including the use of carmustine versus busulfan and thiotepa dosing do not appear to significantly impact outcomes.

Crump:Kyte/Gilead: Honoraria; Roche: Research Funding; Epizyme/Ipsen: Research Funding; Canada's Drug Agency (CADTH): Honoraria. Kridel:Telix Pharmaceuticals: Current equity holder in publicly-traded company; BMS: Research Funding; Acerta Pharma: Research Funding; Eisai: Other: Travel expenses; Roche: Research Funding; AstraZeneca: Research Funding; ITM Isotope Technologies Munich SE: Current equity holder in private company; Abbvie: Research Funding. Bhella:Kite/Gilead: Consultancy, Honoraria. Foley:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Honoraria. Balitsky:Beigene: Honoraria; Kite/Gilead: Honoraria; Sobi: Honoraria; BMS: Honoraria; Novartis: Research Funding. Kuruvilla:DSMB Karyopharm: Other; F. Hoffmann-La Roche Ltd, AstraZeneca, Merck, Novartis: Research Funding; AbbVie, Amgen, AstraZeneca, BMS, Genmab, Gilead, Incyte, Janssen, Merck, Novartis, Pfizer, F. Hoffmann-La Roche Ltd, Seattle Genetics: Honoraria; AbbVie, BMS, Gilead, Merck, F. Hoffmann-La Roche Ltd, Seattle Genetics: Consultancy. Davies:Janssen: Honoraria; Roche: Honoraria; Astra-Zeneca: Honoraria.