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ASCT regimen shows promise for CNS-involved non-Hodgkin’s lymphoma

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December 1, 2014

High-dose rituximab in combination with thiotepa, busulfan and cyclophosphamide for autologous stem cell transplantation appeared safe and effective in patients with non-Hodgkin’s lymphoma and central nervous system involvement, according to phase 2 study results.

“I believe high-dose chemotherapy with autologous stem cell transplantation (ASCT) is the best consolidation therapy for patients with central nervous system non-Hodgkin’s lymphoma,” Yi-Ben Chen, MD, of the bone marrow transplant unit at Massachusetts General Hospital, told HemOnc Today. “Nevertheless, some patients will still experience disease relapse. The motivation for this study was to build upon our positive experience with ASCT and aim to improve our outcomes.”

Chen and colleagues sought to determine whether the addition of high-dose rituximab (Rituxan; Genentech, Biogen Idec) — which has demonstrated activity in primary central nervous system (CNS) lymphoma — to high-dose thiotepa, busulfan (Busulfex, Otsuka Pharmaceutical) and cyclophosphamide would improve outcomes with ASCT.

The analysis included 18 patients with primary CNS non-Hodgkin’s lymphoma and 12 patients with secondary CNS lymphoma who were in partial or complete remission. The median age of patients was 58 years.

Patients received 250 mg/m2 thiotepa, 12 0.8-mg/kg doses of busulfan and two 60-mg/kg doses of cyclophosphamide prior to ASCT. They also received 1,000 mg/m2 rituximab 9 days before ASCT and after the start of thiotepa, and 2 days before ASCT after the completion of cyclophosphamide.

Twenty-nine patients underwent ASCT.

Two patients experienced significant neurotoxicity, including one patient who developed and recovered from thrombotic microangiopathy involving the CNS. The other patient had previously been treated with whole brain radiation therapy and died from continued cognitive decline 5 months post-transplant. No other patients died due to non-relapse causes, which equated to a 0% 100-day non-relapse mortality rate.

“We certainly showed that high-dose rituximab is safe to administer in this fashion and achieves a penetration of approximately 0.1% of plasma levels,” Chen said. “[However], the ultimate answer of if high-dose rituximab can improve outcomes can only be answered in a large randomized trial.”

Median follow-up for surviving patients was 24 months (range, 12-40).

All patients who underwent ASCT achieved engraftment. The median time to neutrophil engraftment was 9 days (range, 8-12) and the median time to platelet recovery was 11 days (range, 8-40).

In the entire cohort, estimated 2-year PFS was 81% (95% CI, 59-92) and 2-year OS was 93% (95% CI, 76-98).

Three patients with secondary CNS lymphoma relapsed after transplant, whereas no patients with primary CNS lymphoma relapsed.

“The results observed in this trial are very favorable compared to the historical experience,” Chen said. “Specifically, for patients with primary CNS non-Hodgkin’s lymphoma, we did not observe any relapses with a median follow-up of 24 months. The clinical implications are that systemic high-dose rituximab may potentially achieve added penetration into the CNS to improve disease control.”

These results may lead to larger randomized trials in this setting, Chen said.

“For patients with primary CNS non-Hodgkin’s lymphoma, there is currently a large prospective multicenter randomized trial asking if ASCT is superior to conventional chemotherapy consolidation,” Chen said. “If this trial shows that ASCT is superior, then we can potentially consider a randomized trial involving high-dose rituximab vs. standard ASCT, provided our data holds up with long-term follow-up. For patients with secondary CNS non-Hodgkin’s lymphoma, this trial adds to the literature showing that CNS disease, if controlled, should not be an obstacle to ASCT. High-dose rituximab may not have as much of a benefit for these patients given that many relapse systemically, and the addition of high-dose rituximab is likely not as significant relative to the increase in the CNS.”

Disclosure: The study was supported in part by Genentech and Otsuka Pharmaceuticals. The researchers report personal fees and institution grants from, as well as advisory/consultant roles with, Amgen, Bayer/Onyx, Flatiron, Genentech, Intervention Insights, Merck, Millennium, Novartis, Otsuka Pharmaceuticals and Seattle Genetics.

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Brad S. Kahl

Brad S. Kahl

Chen and colleagues report the results of a phase 2 trial of high-dose rituximab with high-dose cytarabine mobilization therapy and high-dose thiotepa, busulfan and cyclophosphamide (TBC) autologous stem cell transplantation in patients with central nervous system (CNS) involvement by non-Hodgkin’s lymphoma. This group of investigators from Massachusetts General Hospital and Dana-Farber Cancer Institute previously reported promising results in CNS lymphoma using the TBC conditioning regimen followed by autologous stem cell rescue. In the current report, they hypothesized that high-dose rituximab (Rituxan; Genentech, Biogen Idec), a drug with limited ability to penetrate the CNS, could potentiate the TBC regimen and produce superior outcomes.    
Patients with both primary CNS lymphoma (n = 18) and systemic non-Hodgkin’s lymphoma with CNS involvement (n = 12) were enrolled in this 30-patient trial. Rituximab at a dose of 1,000 mg/m2 was given twice prior to stem cell mobilization. There was no apparent detrimental effect on the ability to mobilize stem cells. High-dose rituximab also was given twice in conjunction with the TBC conditioning regimen. Toxicity did not appear different than what is expected with TBC alone. Engraftment was typical. Most importantly, the efficacy was impressive. Of the 12 patients with systemic lymphoma, the 2-year PFS was 51%. Of the 18 patients with primary CNS lymphoma, the 2-year PFS was 100%.
One cannot help but be struck by these results, particularly in the patients with primary CNS lymphoma. They are very impressive. These data provide additional support for intensive therapy in CNS lymphoma. One cannot truly sort out the contribution of the high-dose rituximab, but these data provide the rationale for further study. Outcomes for patients with primary CNS lymphoma, a disease with a median OS of 12 to 18 months a decade ago, appear to be much better in the current treatment era. Kudos to these investigators for the progress they are making.

Brad S. Kahl, MD
HemOnc Today Editorial Board member
University of Wisconsin Carbone Cancer Center

Disclosure: Kahl reports research funding from and consultant roles with Roche/Genentech.