A New Treatment For Primary Central Nervous System Lymphoma

Research sheds light on a effective new treatment regimen for patients with what had once been considered a universally lethal disease.

Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin's lymphoma subtype where the primary disease site is within the central nervous system. When the disease includes the brain, it is referred to as PCNSL with brain involvement.

Untreated, PCNSL has been shown to be deadly within three or four months of diagnosis. However, in the past 25 years the disease has gone from being unanimously deadly to being highly curable.

The overwhelming majority of patients diagnosed with PCNSL have a disease that at the molecular level looks a lot like diffuse large B-cell lymphoma (DLBCL). Unfortunately, when it came time to treat PCNSL, the conventional DLBCL therapy (R-CHOP) didn't work. Most experts believe this is because PCNSL escapes chemo behind the blood-brain barrier, leading to relapse.

To prevent this, doctors began administering whole-brain radiotherapy (WBRT). While WBRT extended survival in patients, it also led to lethal neurotoxicity in too many patients. When it was combined with high-dose methotrexate-based chemotherapy, doctors found that patients who had been cured by the therapy were dying from the severe toxicity.

Thus, while doctors knew that induction therapy for PCNSL patients would be methotrexate-based, the search was on for the right consolidation therapy, one that could lead to long-term remission in patients without being so devastatingly neurotoxic.

Stunning New Findings

Researchers at Memorial Sloan Kettering Cancer Center in New York, led by Antonio Omuro, may have found it. They published the results of a single-center phase-2 study of newly diagnosed patients with PCNSL that involves high-dose induction immunochemotherapy, followed by high-dose chemotherapy and an autologous stem-cell transplant as consolidation therapy. This new regimen, although only tested in a relatively small sample, displayed an ability to overcome chemoresistance, get past the blood-brain barrier, and lead to durable remissions in this otherwise hard-to-treat patient population.

In the study, published in the journal Blood, patients received between five to cycles of induction immunochemotherapy involving the R-MPV regimen:

• Rituximab
• Methotrexate
• Procarbazine
• Vincristine

[Note: This regimen reflects the historical success of methotrexate against this subtype; the historical success of multi-drug therapy; and the fact that while rituximab doesn't as a rule cross the blood-brain barrier in most patients, it appears to do so in patients with brain lymphoma, when given in unusually high dosages.]

Patients with partial or complete response to R-MPV continued on to consolidation high-dose chemotherapy (HDC) consisting of the TBC regimen, an aggressive regimen known to penetrate the central nervous system:

• Thiotepa
• Busulfan
• Cyclophosphamide

This was in preparation for an autologous stem cell transplant.

End Points

Objective Response Rate

The objective response rate after R-MPV therapy, meaning the percentage of patients who had either partial or complete response to the first round of chemotherapy, was 97 percent.

Progression-Free Survival Rate

The two-year progression-free survival rate after R-MPV therapy, meaning the percentage of patients who, after two years, showed no signs of their disease getting worse, was 79 percent.

Overall Response Rate

The two-year overall survival rate after R-MPV therapy, meaning the percentage of patients who, after two years, are still alive, was 81 percent.

A total of 32 patients were involved in the study. 26 of them also underwent HDC and the stem cell transplant. In these patients, the two-year progression-free survival and overall survival rates were 81 percent. This is significantly higher than any previous therapy and potentially a tremendous breakthrough in the treatment of patients with this disease.

Treatment-Related Questions

The trial didn't go smoothly for every patient. Specifically, there were three treatment-related deaths.

However, researchers determined that for the overwhelming majority of patients in the study, not only is this new treatment highly effective, it also has an acceptable toxicity profile, and does not appear to be neurotoxic.

The team found that PCNSL as a disease, before any treatment, can by itself impair cognitive function. One concern is that treatment can augment impairment so they included, as part of the study, prospective neuropsychological evaluations in the form of neuropsych tests, quality-of-life assessments, and radiographic evaluation of neurotoxicity.

They reported that patients in this study who experienced some cognitive impairment early on were no longer exhibiting any signs of impairment and were in fact gradually getting better.

Sources:
Omuro A, Correa DD, DeAngelis LM, et al. R-MPV followed by high-dose chemotherapy with TBC and autologous stem-cell transplant for newly diagnosed primary CNS lymphoma. Blood 2015;125(9):1403-1410.

Schmitz N. Treatment of Primary CNS Lymphoma. Blood. 2015 Feb 26;125(9):1360-1.