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. 2024 Jun 21;5(4):709-720.
doi: 10.1002/jha2.951. eCollection 2024 Aug.

Sequential high-dose methotrexate and cytarabine administration improves outcomes in real-world patients with primary central nervous system lymphoma: A report from the Australasian Lymphoma Alliance

Maciej Tatarczuch  1   2 , Katharine Louise Lewis  3   4 , Ashray Gunjur  5 , Briony Shaw  1 , Li Mei Poon  6   7 , Erin Paul  8 , Matthew Ku  8   9 , Mark Wong  10 , Sylvia Ai  11 , Ashley Beekman  12 , Pietro R Di Ciaccio  13   14 , Michael Krigstein  13 , Joel Wight  15 , Caitlin Coombes  14   16 , Michael Gilbertson  1   2 , Amanda Tey  17 , Jake Shortt  1   2 , Chandramouli Nagarajan  18   19 , Dipti Talaulikar  14   16 , Nada Hamad  13   20   21 , Sumita Ratnasingam  12 , Shir-Jing Ho  11   22 , Tara Cochrane  10   23 , Eliza A Hawkes  24   25 , Chan Y Cheah  3   26 , Stephen Opat  1   2 , Gareth P Gregory  1   2
Affiliations

Sequential high-dose methotrexate and cytarabine administration improves outcomes in real-world patients with primary central nervous system lymphoma: A report from the Australasian Lymphoma Alliance

Maciej Tatarczuch et al. EJHaem. .

Abstract

Background: Despite recent advances, optimal therapeutic approaches applicable to subpopulations with primary central nervous system (CNS) lymphoma outside of clinical trials remain to be determined.

Methods: We performed a retrospective study of immunocompetent, adult patients with histologically confirmed diffuse large B-cell lymphoma of the CNS (PCNSL). 190/204 (93%) patients (median age: 65) received one of five high-dose methotrexate (HD-MTX) containing chemotherapy regimens: MPV/Ara-C (HD-MTX, procarbazine, and vincristine, followed by cytarabine [Ara-C]) (n = 94, 50%), MATRix (HD-MTX, Ara-C, thiotepa, and rituximab) (n = 19, 10%), HD-MTX/Ara-C (n = 31, 16%), HD-MTX monotherapy (n = 35, 18%) and MBVP (HD-MTX, carmustine, teniposide, prednisolone) (n = 11, 6%).

Results: Cumulative median HD-MTX and Ara-C doses were 17 g/m2 (range: 1-64 g/m2) and 12 g/m2 (0-32 g/m2) respectively. Using 14 g/m2 as the reference dose, the median HD-MTX relative dose intensity (HD-MTX-RDI) was 1.25 (0.27-4.57) with 84% receiving > 0.75. The overall response rate (ORR) was 72% (complete response: 50%) after completing HD-MTX. At a median follow-up of 3.41 years (0.06-9.42), progression-free survival (PFS) and overall survival (OS) were different between chemotherapy cohorts, with the best outcomes achieved in the MPV/Ara-C cohort (2-year PFS 74%, 2-year OS 82%; p = 0.0001 and p = 0.0024 respectively). On multivariate analysis, MPV/Ara-C administration and HD-MTX-RDI > 0.75 were associated with longer PFS and OS.

Conclusion: Sequential, response-adapted approaches can improve outcomes, even in older patients who are ineligible for a high-intensity concurrent chemotherapy approach and do not undergo traditional consolidative strategies.

Keywords: DLBCL; PCNSL; cytarabine; high‐dose therapy; methotrexate; retrospective studies.

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Conflict of interest statement

Katharine Louise Lewis: Consultancy/Honoraria: Jansen Roche. Trial steering committee: Loxo/Lilly. Advisory: IQVIA and MSD; Pietro R. Di Ciaccio: Honoraria/travel funding: Janssen, Astra Zeneca, and Gilead/Kite; Chan Y. Cheah: Research funding: Beigene. Advisory: Janssen Cilag. Joel Wight: Honoraria: Janssen, MDI, Beigene, MSD, and Abbvie. Travel support: Kite/Gilead. Jake Shortt: Consultancy: BMS, Otsuka, Pfizer, and Astellas. Speaker's Bureau: Mundipharma and Novartis. Research funding: Astex. Dipti Talaulikar: Consultancy/Advisory/Honoraria: Roche, Janssen, Beigene, Novartis, Amgen, Antengene, CSL, EUSA, BMS, and Takeda. Research funding: Roche, Janssen, and Takeda. Tara Cochrane: Research funding: Beigene. Advisory: Janssen Cilag. Eliza A. Hawkes: Consultancy/Advisory: AstraZeneca, Janssen Oncology, Merck Sharpe & Dohme, Gilead Sciences, Bristol Myers Squibb, Novartis, Beigene, Link Healthcare, and Regeneron. Speaker's Bureau: Roche/Genentech, Regeneron, and Abbvie. Research funding: AstraZeneca, Celgene, Merck KGaA, Janssen‐Cilag, Gilead Sciences, Mundipharma, Bristol‐Myers Squibb, and Roche/Genentech. Travel: AstraZeneca.

Figures

FIGURE 1
FIGURE 1
Consort diagram. MPV/Ara‐C: methotrexate, procarbazine, vincristine, followed by cytarabine. MATRix: methotrexate, cytarabine, thiotepa, rituximab. Methotrexate (HD‐MTX)/cytarabine (Ara‐C): methotrexate, cytarabine (+/‐ rituximab). HD‐MTX: methotrexate (+/‐ rituximab). MBVP: methotrexate, carmustine, teniposide, prednisolone (+/‐ rituximab) [patients enrolled in HOVON105/ALLG NHL4 study] [16]. HIV VL, human immunodeficiency virus viral load; non‐DLBCL, non‐diffuse large B‐cell lymphoma histology; PTLD, post‐transplant lymphoproliferative disorder; R, rituximab; WBRT, whole brain radiotherapy. Fourteen patients (7%) did not receive HD‐MTX‐containing chemotherapy. These patients were older than those who received HD‐MTX‐containing chemotherapy (72 years [range: 63–85] vs. 67 years [25‐87]; p = 0.001). Incomplete follow‐up data precluded progression‐free survival (PFS) and overall survival (OS) estimates in this cohort.
FIGURE 2
FIGURE 2
Survival graphs. Median follow‐up: 3.41 years (0.06–9.42). (A) Progression‐free survival and (B) Overall Survival of high‐dose methotrexate (HD‐MTX) cohort [all regimens]. (C) Progression‐free survival and (D) Overall survival by chemotherapy cohort. (E) Progression‐free survival and (F) Overall survival by seven versus five cycles of MPV.
FIGURE 3
FIGURE 3
Survival graphs. Median follow‐up: 3.41 years (0.06–9.42). (A) Progression‐free survival and (B) Overall survival by age. (C) Progression‐free survival and (D) Overall survival by consolidative whole brain radiotherapy (WBRT) versus no consolidative WBRT (dose 20–45 Gy). Patients who received WBRT for relapsed/refractory disease or consolidative ASCT were excluded from the analysis.
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