Pemetrexed in the Treatment of Relapsed/Refractory Primary Central Nervous System Lymphoma

By Mamatha Prabhakar, MD, Hematology/Oncology Division, IASIA-Falls Church, VA. Dr. Prabhakar reports no financial relationships relevant to this field of study.

Synopsis: In this Phase 2 trial, 11 patients with relapsed/refractory primary central nervous system lymphoma after high-dose, methotrexate-based regimen were treated with pemetrexed 900 mg/m2 every 3 weeks, dexamethasone 4 mg bid, folate, and B12 supplementation. The treatment had an overall response rate of 55%, disease control rate of 91%, median progression free survival of 5.7 months, and median overall survival of 10.1 months. Toxicities were more than expected with the standard pemetrexed dose (500 mg/m2) and were primarily hematologic and infectious, which were easily managed. Although single-agent activity of pemetrexed in this study is novel and promising, optimal dosing and efficacy need to be studied further.

Source: Raizer JJ, et al. Pemetrexed in relapsed/refractory PCNSL. Cancer 2012;118:3743-3748.

Nearly one-half of primary central nervous system lymphomas (PCNSL) occur in patients older than 60 years and about 90% are diffuse large B cell lymphomas. Although R-CHOP is effective for systemic lymphoma, similar approaches for PCNSL have failed to produce durable disease control. Untreated patients survive only a few months. Although whole-brain radiation therapy improves survival, it is associated with significant neurologic toxicity and its use is limited. High-dose, methotrexate-based regimens have demonstrated superior overall survival of 30-50 months.1 However, despite this, PCNSL almost uniformly results in recurrence or progression and death. Expectant survival after relapse is about 4-8 months.2 No standard salvage treatment for relapsed or refractory disease exists. Although numerous approaches including radiation, chemotherapy (temozolamide, etoposide), and/or rituximab have been attempted, these have resulted in variable degrees of demonstrable activity. With the poor outcomes linked to PCNSL, there is a constant quest to identify a novel agent that is effective, safe, and easy to administer. Pemetrexed is a rational strategy for therapeutic palliation of recurrent or progressive PCNSL. Its mechanism of action is similar to methotrexate but it has the advantage of targeting more than one site of folate synthesis, convenient administration, single-agent efficacy, established management algorithms, outpatient administration, and its evidence of safety and efficacy in systemic malignancies. The authors conducted this trial using pemetrexed in patients with relapsed/refractory PCNSL to determine single-agent activity. Enrolled subjects had a Karnofsky performance of > 60. Based on preclinical data suggesting limited penetration into the central nervous system, a dose higher than standard (900 mg/m2 rather than 500 mg/m2) was chosen.3 Eleven patients were treated on 6-week cycles with pemetrexed 900 mg/m2 administered on days 1 and 21. Patients received dexamethasone 4 mg bid on the day before, the day of, and the day after each infusion of pemetrexed, and all patients were supplemented with folic acid and B12. Patients remained on the treatment until disease progression or intolerable side effects occurred. Those attaining CR received two additional doses. MRI was done every 6 weeks.

The authors observed a CR rate of 36%, PR rate of 19%, overall response rate (CR+PR) of 55%, and a disease control rate (CR+PR+SD) of 91%, all of which match favorably with other tested novel agents (e.g., temozolomide single-agent: relative risk [RR] 31%, progression-free survival [PFS] 2.8 months, and overall survivial [OS] 3.9 months).4 The PFS at 6 months and 12 months were 45% (95% confidence interval [CI], 16%-74%) and 27% (95% CI, 20%-70%), respectively, with a median PFS of 5.7 months (95% CI, 1.6-21.4 months). The median OS was 10.1 months (95% CI, 2.4-33.3 months). Most common toxicities were hematologic (cytopenias), including one patient with neutropenic pneumonia. One patient had dose reduction for hematologic toxicity and one patient discontinued due to grade 3 thrombocytopenia. The authors believe the toxicities seen in this study were related to using higher than standard dose (900 mg/m2).

Commentary

Despite the aggressive upfront use of high-dose, methotrexate-based chemotherapy, PCNSL almost uniformly results in recurrence, progression, and death. Its rare presentation, incomplete molecular and biological understanding, and difficulty in execution of prospective trials has limited the identification of new therapeutic agents. Despite these unfavorable features, there has been progress, and different agents have been tried with comparable activity including temozolomide, etoposide, rituximab, and now pemetrexed. Although combination salvage regimens like PCV (procarbazine, CCNU, vincristine) have shown higher response rates (86%) and OS of 16 months, these have proven difficult to administer because of associated increased toxicity. It is interesting to note that pemetrexed showed single-agent activity in patients who had failed earlier high-dose methotrexate therapy. All patients also received dexamethasone during pemetrexed treatment and this might have contributed to the response rates. Preclinical studies have shown limited CNS penetrance for pemetrexed, although slightly better than methotrexate. Its easy outpatient administration is an advantage over other agents that require hospitalization. With the use of higher doses of pemetrexed (900 mg/m2) to improve CNS penetration, toxicities seen were more than expected. In future clinical trials using high-dose pemetrexed, it will be interesting to see if leucovorin instead of folic acid will be able to minimize the toxicities. If pemetrexed is chosen for treatment, pneumocystis prophylaxis should be considered, as two of 11 patients developed PCP pneumonia. Clinical trials testing higher doses of pemetrexed are underway and might add more information on the pharmacokinetics, improved CNS penetration, and safety.

References

1. Ferreri AJ, et al. High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: A randomised Phase 2 trial. Lancet 2009;374:1512-1520.

2. Jahnke K, et al. Relapse of primary central nervous system lymphoma: Clinical features, outcome, and prognostic factors. J Neurooncol 2006;80:159-165.

3. Stapleton SL, et al. Plasma and cerebrospinal fluid pharmacokinetics of pemetrexed after intravenous administration in non-human primates. Cancer Chemother Pharmacol 2007;59:461-466.

4. Reni M, et al. Salvage chemotherapy with temozolomide in primary CNS lymphomas: Preliminary results of a phase II trial. Eur J Cancer 2004;40:1682-1688.