Researchers have for the first time shown that high-dose chemotherapy consolidation is safe and feasible in the multicenter, cooperative group setting for newly diagnosed primary CNS lymphoma patients.
Previously, the Radiation Therapy Oncology Group had shown that a combined-modality approach using high-dose methotrexate-based chemotherapy followed by whole-brain radiotherapy significantly extended median progression-free survival (PFS) to two years. However, concerns regarding neurocognitive toxicity of whole-brain radiotherapy motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma.
“At this point I would recommend that no patient with primary CNS lymphoma be treated with whole-brain irradiation as consolidation in first remission,” said the lead author of a multicenter study of the technique, James Rubenstein, MD, PhD, Professor in the Department of Medicine at the University of California, San Francisco. “There is enough evidence that whole-brain radiotherapy has irreversible and severe neurotoxicities that do not appear to be elicited with high-dose chemotherapeutic approaches.”
In the study, published in the September 1 issue of the Journal of Clinical Oncology ( 2013;31:3061-3068 ), he and colleagues performed a multicenter, Phase II study (CALGB 50202) of high-dose consolidation without whole-brain irradiation in patients without primary CNS lymphoma. The team determined the rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R), and noted the feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA).
Patients who achieved a CR then received EA consolidation. The researchers also performed a prospective analysis of molecular prognostic biomarkers in the setting of a clinical trial. Virtually all (98%) of the patients, median age of 61, had large B-cell lymphoma.
“The most appropriate primary CNS lymphoma candidates for high-dose chemotherapy consolidation therapy are patients younger than 75 who are fit enough to tolerate dose-intensive chemotherapy,” Rubenstein said. “Remarkably, the PFS of patients over age 60 years was similar compared with that of younger patients—a result that contrasts with previous studies in primary CNS lymphoma.”
He said that although preliminary, this observation does suggest that many of the established prognostic features of the disease may be dependent on treatment-related variables, including radiotherapy. In addition, there may be subgroups of patients with primary CNS lymphoma for whom radiotherapy may be necessary and who may potentially be identified in randomized studies.
Although median overall survival has not been reached, the researchers calculated an estimated 0.65 probability for that at four years. There have been 17 deaths, and median survival among the other 27 patients was 4.9 years.
The regimen was generally well-tolerated, he said, with the exception of one treatment-related death caused by sepsis in a patient treated as an outpatient after having EA chemotherapy.
“This event highlights the recommendation of detailed inpatient monitoring during the neutropenic and thrombocytopenic nadirs expected after the intensive consolidation phase of treatment. On the other hand, myelosuppression during the remission induction phase was mild; few patients required growth factor support; and there was only one case of grade 3 renal toxicity, despite the high doses of methotrexate administered.”
Although there were no reported episodes of severe acute neurotoxicity, detailed post-treatment neurocognitive testing was not performed, he noted.
Treatment delay was associated with an adverse outcome. More than half of the patients with more than 30 days of delay in treatment initiation died from their lymphoma, compared with less than 30 percent of patients who started treatment within 30 days—“This has important implications for the management of these patients, and provides evidence that the prompt initiation of therapy after diagnosis may translate to improved outcomes in primary CNS lymphoma.”
Interventions that facilitate early diagnosis of primary CNS lymphoma and intraocular lymphoma may also translate into improved outcomes for patients, Rubenstein added. Several factors contribute to having a delayed start after diagnosis, such as community practitioners perhaps not being familiar with the therapeutic options, patients choosing to delay treatment to obtain a second opinion, and the assumption that the disease is incurable.
Also found was that a high expression of BCL6 in newly diagnosed patients correlated with shorter survival, suggesting, he said, that this biomarker could prospectively be used in risk-adapted therapy, and that rational application of antagonists to this marker could be used in treatment.
“The MT-R EA regimen is well-tolerated and I believe appropriate therapy for the majority of primary CNS lymphoma patients,” Rubenstein said. “Efficient diagnosis, staging, and initiation of therapy may lead to improved outcomes.”
On the basis of these encouraging results, he said, an intergroup study has now begun to compare the use of EA consolidation with myeloablative chemotherapy in a randomized trial in primary CNS lymphoma, in which neither arm involves whole-brain irradiation.
“With the intergroup study, we will begin to learn about the relative efficacies and relative toxicities of distinct high-dose consolidative regimens in patients who receive a uniform induction regimen that is well-tolerated,” he said. “A number of important correlative studies are being performed as well that will provide further insight into prognostic risk groups, and I hope facilitate the development of risk-adapted therapies.”
In an accompanying editorial (JCO:2013;31:3051-3053), Tracy T. Batchelor, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, said that “a sound scientific rationale was employed for the selection of the drugs in the induction and consolidation regimens employed in the trial.” Each of the drugs selected for the MT-R induction regimen had demonstrated safety and efficacy as a single agent in prior clinical studies in patients with either newly diagnosed or relapsed primary CNS lymphoma. EA had previously been combined as effective salvage therapy in a study of patients with relapsed disease.
He called the results of the trial—a median progression-free survival time of four years, and 59 percent of patients remaining progression free at two years—“impressive achievements, comparable with or superior to results obtained in other prospective, multicenter trials with regimens that included whole-brain irradiation as consolidative therapy.”
An important observation, Batchelor continued, was that a delay in starting induction chemotherapy had a detrimental effect on tumor response and outcomes—“This observation highlights the importance of early diagnosis and prompt initiation of chemotherapy in patients diagnosed with primary CNS lymphoma.”
He was more cautious about the BCL6 findings: “Although BCL6 expression might be a marker of a more resistant subtype of primary CNS lymphoma, these results should be interpreted with caution as they are based on tumor specimens from 26 patients, and previous reports of BCL6 expression in primary CNS lymphoma have yielded conflicting results with respect to outcomes,” he wrote.
Batchelor commended the authors' effort, which raises new questions and sets the stage for subsequent clinical trials to build on their success. “An important question is whether this induction regimen can be intensified to increase the proportion of patients experiencing CR before consolidation,” he wrote.
“Another question is whether the results achieved with EA consolidation could be improved by substitution of high-dose chemotherapy followed by autologous stem-cell transplantation—a consolidative strategy that has achieved encouraging results in a prospective, multicenter Phase II study.”
The latter question, he noted, will be answered by the ongoing, intergroup, randomized trial in which all patients with primary CNS lymphoma are being treated with induction MT-R followed by consolidative EA versus high-dose chemotherapy and autologous stem-cell transplantation.
This study, he said, includes correlative biospecimen, imaging, neurocognitive, and quality-of-life studies in an effort to better understand patient outcomes, including the short-term and long-term consequences of these treatments on the growing proportion of long-term survivors with primary CNS lymphoma.