麻豆传媒

NEW ORLEANS -- High-dose chemotherapy followed by transplant as consolidation treatment for primary central nervous system (CNS) lymphoma prolonged survival compared with a non-myeloablative regimen, an international phase III trial showed.

Among 229 patients with newly diagnosed disease who had responded to induction therapy, progression-free survival (PFS) rates at 3 years reached 79% with high-dose chemotherapy plus autologous stem-cell transplant (ASCT) consolidation, as compared with 53% with a non-myeloablative chemoimmunotherapy regimen (HR 0.405, 95% CI 0.252-0.650, P=0.0002), reported Gerald Illerhaus, MD, of Klinikum Stuttgart hospital in Germany.

And with a median follow-up of 45.3 months, 86% versus 71% of patients were still alive, respectively (HR 0.456, 95% CI 0.256-0.812, P=0.0077), according to findings presented during a late-breaking session at the American Society of Hematology annual meeting.

"Treatment of primary CNS lymphoma is particularly challenging. It's an aggressive lymphoma entity with a unique localization," said Illerhaus, noting that drug delivery is impeded by the blood-brain barrier. "The surrounding tissue reacts very sensitively both to the lymphoma itself and to the therapy, regardless of whether it is chemotherapy or radiation."

Patients in the high-dose chemotherapy group received carmustine (or busulfan if not available) and thiotepa followed by ASCT, while those in the non-myeloablative consolidation arm received two cycles of R-DeVIC (rituximab, high-dose dexamethasone, etoposide, ifosfamide, and carboplatin).

"This is hugely impactful and practice-changing as of today," Joshua Brody, MD, director of the Lymphoma Immunotherapy Program at the Tisch Cancer Institute at Mount Sinai in New York City, told 麻豆传媒.

He noted that no randomized trials in the past two decades have meaningfully impacted the standard of care for patients with brain lymphoma, while the current study demonstrated a 15% absolute difference in overall survival at 3 years with high-dose chemotherapy followed by transplant, when compared with another "pretty reasonable" regimen.

"That's a big deal, that's life and death. That is the gold standard of all cancer research," said Brody, who was not involved in the study.

In America, according to Brody, these patients have typically received methotrexate-based regimens, with or without transplant, but this has largely been supported by single-arm data due to it being extremely difficult to conduct clinical trials for this disease.

"There's great heterogeneity of care, because none of the standards have been high-level evidence," he said. "They've always been, 'Well, one center got good results with this regimen, so we'll use their regimen.' That's not the way we like to practice medicine."

In the current study, all subgroups showed a PFS advantage with the high-dose chemotherapy/ASCT strategy, said Illerhaus, and PFS and overall survival were significantly superior to conventional immunochemotherapy with R-DeVIC, "despite similar remission rates after consolidation."

Following induction, complete and partial response rates were about 40% and 60%, respectively, for each of the two arms. And as noted, improvements in response during the randomized period were also similar for the high-dose chemotherapy/ASCT and R-DeVIC groups:

• Complete responses: 67.5% vs 65.2%, respectively
• Partial responses: 21.1% vs 15.7%

A limitation of the trial, Brody highlighted, was that patients were mostly younger (65 and under), with patients up to age 70 included if they were fit.

"You might still choose to give this regimen to a 71-year-old," he said. "That is how medicine happens, you have to sometimes flex the regimen a little bit from the textbook."

Toxicity was higher with the high-dose chemotherapy/ASCT strategy, and during a Q&A session following the presentation Illerhaus suggested that ASCT may not be appropriate for frail patients. He said future studies should look at whether circulating tumor DNA can help avoid overtreatment in these patients.

It is "not gentle therapy," said Brody, noting that 3% to 4% of patients in the high-dose chemotherapy/ASCT arm died during the course of therapy.

"Stem-cell transplant, that might sound elegant, but it really is just such high-dose chemotherapy that we have to give you stem cells back afterwards to save you," he said. "But it is impactful, and if I got brain lymphoma tomorrow or a relative of mine did, and they were young-ish and healthy-ish, I would unquestionably give them this regimen, because I have no other regimen to point at that I could say the evidence is as good."

Also during the Q&A, Andrew Zelenetz, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, observed that the survival curves "start to separate after 2 years, which in systemic large-cell lymphoma we think of as the point where we can stop worrying about many relapses."

Zelenetz asked whether the researchers had been able to look at minimal residual disease (MRD) or other markers of response to try to understand this separation.

"It's really a very interesting finding," said Illerhaus, who said the researchers had collected "material" from the patients and would conduct further analyses to evaluate potential markers of long-term response.

From 2014 to 2019, the phase III enrolled patients from 79 centers across five European countries (Germany, Italy, Denmark, Norway, and Switzerland). Inclusion criteria were as follows: immunocompetent adults ages 18-65, irrespective of performance status, or ages 66-70 with an Eastern Cooperative Oncology Group (ECOG) score of 2 or lower; a confirmed B-cell lymphoma; one radiographically measurable lesion; and adequate organ function.

Overall, 346 patients started induction therapy, which consisted of four cycles of MATRix (rituximab, methotrexate, cytarabine, and thiotepa). Stem cell harvesting was performed after cycle two, and patients with progressive disease after two or four cycles were treated off study. A total of 53 became ineligible for consolidation due to adverse events, 40 for non-response, and 23 for other reasons. Treatment-related mortality occurred in 13 patients (3.8%).

Illerhaus noted that the randomized trial is currently testing a gentler induction strategy with the hopes of reducing toxicity rates.

Ultimately, the 229 responding patients were randomized to consolidation with either high-dose chemotherapy followed by ASCT, or non-myeloablative chemoimmunotherapy with R-DeVIC, a regimen that has been shown to be effective in and uses non-cross-resistant agents compared with MATRix.

Among the randomized participants, median age was 59-60, with 20%-24% being 65 or older, women made up 43%-46% of the population, and three-fourths had an ECOG performance status of 0-1. Diffuse large B-cell lymphoma was the primary histology in nearly all (97%-98%), about one-third had increased low-density lipoprotein cholesterol, 41% had increased cerebrospinal fluid (CSF) protein, 4% had meningeal involvement, and about 60% had multiple lesions.

Grade 3/4 adverse events were more frequent with high-dose chemotherapy/ASCT versus the non-myeloablative chemoimmunotherapy, including thrombocytopenia (95% vs 83%, respectively), neutropenia (75% vs 56%), anemia (75% vs 69%), febrile neutropenia/infections (63% vs 15%), infections (53% vs 14%), oral mucositis (55% vs none), vascular disorders (9% vs 3%), cardiac disorders (3% vs none), and renal toxicity (5% vs none). No differences were seen for nervous system disorders (5% in each arm) or neurotoxicity.

During randomization, 3.4% of patients died in the high-dose chemotherapy/ASCT arm due to treatment-related toxicity versus none in the R-DeVIC arm.

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