Induction therapy

High-dose methotrexate.[8-13] Outside of clinical trials, high-dose methotrexate is the most frequently used standard induction therapy.[14] However, it is given to inpatients, and it is too toxic for patients with a creatinine clearance under 35 cc/min or for most patients older than 75 years.

Lenalidomide with rituximab.[15] When high-dose chemotherapy is not feasible, this is the most frequently used combination. Lenalidomide can be initiated at low doses (e.g., 5 mg daily, 21 out of 28 days) in patients with renal insufficiency.

High-dose cytarabine.[12,13,16]

Rituximab.[16-18]

Thiotepa.[18,19]

Temozolomide.[20]

Ibrutinib.[21,22]

Procarbazine.[23]

Vincristine.[23]

Pomalidomide.[24]

Nivolumab.[25]

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

With a median follow-up of 88 months, the overall survival (OS) rate was 21% for group 1, 37% for group 2, and 56% for group 3.

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

Group 1 versus group 2: hazard ratio (HR), 0.64; 95% confidence interval (CI), 0.41–0.99; P = .04.

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

Group 1 versus group 3: HR, 0.42; 95% CI, 0.24–0.64; P = .00005.

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

Group 2 versus group 3: HR, 0.66; 95% CI, 0.44–0.98; P = .04.

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

The 113 patients who attained a complete response, partial response, or stable disease were randomly assigned to 36 Gy whole-brain radiation therapy versus autologous stem cell transplant (SCT) after thiotepa + bic-chloroethylnitrosourea + carmustine (BCNU) conditioning. No significant differences were seen in 7-year progression-free survival (PFS) or OS in regard to consolidation in this phase II trial.[26][Level of evidence B1]

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

The thiotepa + BCNU conditioning regimen was well tolerated by patients aged 60 to 70 years. It had improved tolerability compared with prior reports using the more intensive thiotepa + busulfan regimen.[26][Level of evidence D]

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

Patients who received the two-drug combination had a complete remission rate of 23% (interquartile range [IQR], 14%‒31%; HR, 0.46; 95% CI, 0.28‒0.74). Patients who received the three-drug combination had a complete remission rate of 30% (IQR, 21%‒42%; HR, 0.61; 95% CI, 0.40‒0.94). Patients who received the four-drug MATRix combination had a complete remission rate of 49% (95% CI, 38%‒60%).

The International Extranodal Lymphoma Study Group evaluated three different induction combinations in 227 patients with newly diagnosed, HIV-negative primary CNS lymphoma. Patients were randomly assigned to receive high-dose methotrexate (HD MTX) + high-dose cytarabine (HDA) (group 1), HD MTX + HDA + rituximab (R) (group 2), or HD MTX + HDA + R + thiotepa (the MATRix regimen) (group 3).[26][Level of evidence A1]The groups were compared as follows:The OS rate favored the complete MATRix regimen in all comparisons.[26][Level of evidence A1]

The addition of rituximab and thiotepa to high-dose methotrexate plus cytarabine resulted in a significant improvement in complete response, PFS, and OS.[26][Level of evidence A1]

In a randomized, nonblinded multicenter trial, 79 patients were assigned to receive high-dose methotrexate with or without cytarabine.[27][Level of evidence B1]

In a randomized, nonblinded multicenter trial, 79 patients were assigned to receive high-dose methotrexate with or without cytarabine.[27][Level of evidence B1]

The 3-year PFS rate was better for patients who received the two-drug regimen (HR, 0.54; 95% CI, 0.31–0.92; P = .01).

In a randomized, nonblinded multicenter trial, 79 patients were assigned to receive high-dose methotrexate with or without cytarabine.[27][Level of evidence B1]

There was no statistical difference in the 3-year OS rate (46% for the two-drug regimen vs. 32% for the one-drug regimen; HR, 0.65; 95% CI, 0.38–1.13; P = .07).

In a randomized, nonblinded multicenter trial, 79 patients were assigned to receive high-dose methotrexate with or without cytarabine.[27][Level of evidence B1]

This trial was the basis for setting the combination of high-dose methotrexate and high-dose cytarabine as the control arm in the MATRix trial.

In a randomized, prospective, multicenter trial, 200 patients were assigned to receive intravenous high-dose methotrexate, carmustine, teniposide, and oral prednisone with or without rituximab.[28][Level of evidence B1]

In a randomized, prospective, multicenter trial, 200 patients were assigned to receive intravenous high-dose methotrexate, carmustine, teniposide, and oral prednisone with or without rituximab.[28][Level of evidence B1]

With a median follow-up of 32.9 months, there was no difference in the 1-year event-free survival (EFS) rate: 52% with rituximab (95% CI, 42%−61%) and 49% without rituximab (95% CI, 39%−58%; HR, 1.00; 95% CI, 0.70−1.43; P = .99).

Several other combination induction regimens were created empirically and presented as phase II trials.[29][Level of evidence C3]

Several other combination induction regimens were created empirically and presented as phase II trials.[29][Level of evidence C3]

Rituximab + high-dose methotrexate + procarbazine + vincristine (R-MPV) (objective response rate, 97%; complete response, 66%)[23].

Several other combination induction regimens were created empirically and presented as phase II trials.[29][Level of evidence C3]

High-dose methotrexate + rituximab + temozolomide (HD MTX + R + TEM) (objective response rate, 80%; complete response, 66%).[20]

Several other combination induction regimens were created empirically and presented as phase II trials.[29][Level of evidence C3]

High-dose methotrexate ± rituximab (HD MTX ± R) + other chemotherapy (retrospective analysis of 885 patients) (objective response rate, 59%; complete response, 50%).[29]