Phase II Trial of Temsirolimus for Relapsed/Refractory Primary CNS Lymphoma

Abstract

Purpose In this phase II study (NCT00942747), temsirolimus was tested in patients with relapsed or refractory primary CNS lymphoma (PCNSL). Patients and Methods Immunocompetent adults with histologically confirmed PCNSL after experiencing high-dose methotrexate-based chemotherapy failure who were not eligible for or had experienced high-dose chemotherapy with autologous stem-cell transplant failure were included. The first cohort (n = 6) received 25 mg temsirolimus intravenously once per week. All consecutive patients received 75 mg intravenously once per week. Results Thirty-seven eligible patients (median age, 70 years) were included whose median time since their last treatment was 3.9 months (range, 0.1 to 14.6 months). Complete response was seen in five patients (13.5%), complete response unconfirmed in three (8%), and partial response in 12 (32.4%) for an overall response rate of 54%. Median progression-free survival was 2.1 months (95% CI, 1.1 to 3.0 months). The most frequent Common Toxicity Criteria ≥ 3° adverse event was hyperglycemia in 11 (29.7%) patients, thrombocytopenia in eight (21.6%), infection in seven (19%), anemia in four (10.8%), and rash in three (8.1%). Fourteen blood/CSF pairs were collected in nine patients (10 pairs in five patients in the 25-mg cohort and four pairs in four patients in the 75-mg cohort). The mean maximum blood concentration was 292 ng/mL for temsirolimus and 37.2 ng/mL for its metabolite sirolimus in the 25-mg cohort and 484 ng/mL and 91.1 ng/mL, respectively, in the 75-mg cohort. Temsirolimus CSF concentration was 2 ng/mL in one patient in the 75-mg cohort; in all others, no drug was found in their CSF. Conclusion Single-agent temsirolimus at a weekly dose of 75 mg was found to be active in relapsed/refractory patients with PCNSL; however, responses were usually short lived.

m‐TOR inhibitors and their potential role in haematological malignancies

“…The most common adverse events (AEs) were haematological, with thrombocytopenia occurring in all patients and being the most frequent cause of dose reductions, although it usually resolving in one week. Unfortunately, the relatively high RR (54%) observed did not translate into a longer PFS (median PFS 2Á1 months), which was comparable with other studies (Korfel et al, 2016). In order to reduce these events, temsirolimus was tested in the same setting in another study at a lower dose of 25 mg/m 2 weekly.…”

“…Other reported toxicities were hyperglycaemia, increased triglycerides, mucositis and fatigue (Witzig et al, 2005). The authors concluded that frequent administration of steroids before response assessment as well as preferential inclusion of elderly patients could be potential confounding factors for response evaluation and outcome (Korfel et al, 2016). The ORR was similar (41%) and severe thrombocytopenia was less common (100% vs. 39%) (Ansell et al, 2008).…”

Ibrutinib Unmasks Critical Role of Bruton Tyrosine Kinase in Primary CNS Lymphoma

“…Ibrutinib compared favorably to other therapies explored in this setting, including the mTOR inhibitor temsirolimus (PFS 2.1 months)(38), the combination of rituximab and temozolomide (PFS 1.6 months)(39), or topotecan (PFS 2 months)(40). While most PCNSL patients eventually developed resistance to ibrutinib, as seen with other kinase inhibitors in cancer (41), further evaluation of ibrutinib as part of combination therapies for PCNSL seems warranted.…”

Biology of CNS lymphoma and the potential of novel agents

“…Median PFS was 2.1 months. 34 Toxicity with temsirolimus is a concern, and a treatment-related mortality rate of 13.5%, mainly due to pneumonia, was observed. A phase 2 trial involving the pan PI3K/MTOR inhibitor, PQR309, for patients with relapsed PCNSL, is now accruing.…”