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LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.
An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.
IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.
So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.
Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).
Treatment and toxicity
The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:
- Arm A consisted of 4 cycles of methotrexate (3.5 g/m2) on day 1 and cytarabine (2 g/m2) twice a day on days 2 and 3 every 3 weeks.
- Arm B added rituximab (375 mg/m2) on days 5 and 0 to the regimen.
- Arm C added rituximab and thiotepa (30 mg/m2) on day 4 to the regimen.
Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.
Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.
Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.
“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”
Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.
Response rates
The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.
“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”
Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.
This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.
The investigators also analyzed activity according to IELSG risk.
“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”
Second randomization and survival
One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.
Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.
At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.
Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.
Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.
Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.
The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection. 
site of 13-ICML
LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.
An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.
IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.
So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.
Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).
Treatment and toxicity
The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:
- Arm A consisted of 4 cycles of methotrexate (3.5 g/m2) on day 1 and cytarabine (2 g/m2) twice a day on days 2 and 3 every 3 weeks.
- Arm B added rituximab (375 mg/m2) on days 5 and 0 to the regimen.
- Arm C added rituximab and thiotepa (30 mg/m2) on day 4 to the regimen.
Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.
Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.
Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.
“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”
Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.
Response rates
The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.
“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”
Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.
This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.
The investigators also analyzed activity according to IELSG risk.
“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”
Second randomization and survival
One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.
Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.
At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.
Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.
Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.
Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.
The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.
site of 13-ICML
LUGANO—Adding thiotepa and rituximab to the treatment of primary central nervous system (CNS) lymphoma is feasible from a safety perspective and has yielded promising results, according to new research.
An analysis of the IELSG 32 trial—in which patients received methotrexate and cytarabine alone, with rituximab, or with rituximab and thiotepa—has shown the 4-drug regimen improves responses and progression-free survival.
IELSG 32 builds on the foundation of the IELSG 20 trial to determine the best induction therapy for patients with primary CNS lymphoma. In IELSG 20, the complete response (CR) rate was higher among patients receiving high-dose methotrexate and cytarabine than in patients receiving methotrexate alone.
So the researchers decided to investigate whether rituximab and/or thiotepa added to the regimen would impact patient outcome. Rituximab has been associated with improved CR rates in primary CNS lymphoma, and thiotepa is active against aggressive lymphomas. Thiotepa is also able to cross the blood–brain barrier.
Andrés J.M. Ferreri, MD, of IRCCS Ospedale San Raffaele in Milan, Italy, reported the results of this research on behalf of the International Extranodal Lymphoma Study Group (IELSG) at the 13th International Conference on Malignant Lymphoma (abstract 009).
Treatment and toxicity
The investigators randomized 227 patients from 53 centers in 5 countries to 4 cycles of treatment in 3 cohorts:
- Arm A consisted of 4 cycles of methotrexate (3.5 g/m2) on day 1 and cytarabine (2 g/m2) twice a day on days 2 and 3 every 3 weeks.
- Arm B added rituximab (375 mg/m2) on days 5 and 0 to the regimen.
- Arm C added rituximab and thiotepa (30 mg/m2) on day 4 to the regimen.
Eight patients were excluded for various reasons, including incorrect diagnosis. So 219 patients received therapy, 75 in arm A, 69 in arm B, and 75 in arm C.
Patients were a median age of 58 years in arm A and 57 in arms B and C, and the majority were male. More than 80% of patients in all arms were intermediate- or high-risk according to IELSG. And all patients had the diffuse large B-cell lymphoma histotype.
Patients in arm A received 74% of the planned courses, those in arm B received 86%, and those in arm C received 91%. The relative dose intensity across all arms of each drug administered was not significantly different among the arms.
“As expected, hematologic toxicity was common, with grade 4 neutropenia (P=0.01) and thrombocytopenia (P=0.0001) being significantly more common for arm C,” Dr Ferreri said. “However, this was not associated with an increasing array of severe infections, interruptions, toxicity, or toxic deaths.”
Peripheral blood stem cell collection was successful in 94% of patients in arms A and C and 96% of patients in arm B.
Response rates
The overall response rate (ORR) was 72% in IELSG 32, compared to 54% in IELSG 20. But the CR rate was not significantly higher in IELSG 32 than in IELSG 20, at 34% and 31%, respectively.
“There are many explanations for this,” Dr Ferreri said. “But I think it was because there were a significantly greater number of patients with higher IELSG risk [in IELSG 32], a higher proportion of poor-prognosis patients.”
Patients in arm C had significantly higher response rates than patients in the other 2 arms, with a CR rate of 49%, a partial response (PR) rate of 37%, and an ORR of 87%.
This compared to a CR rate of 23% in arm A and 30% in arm B, a PR rate of 31% in arm A and 30% in arm B, and an ORR of 53% in arm A and 74% in arm B.
The investigators also analyzed activity according to IELSG risk.
“Arm C was significantly more active in all the 3 subgroups,” Dr Ferreri observed, “and importantly, the overall response rate and complete remission rate were similar for each arm in the 3 different risk groups.”
Second randomization and survival
One hundred and eighteen patients went on to a second randomization, 35 from arm A, 35 from arm B, and 48 from arm C.
Fifty-nine patients were randomized to the whole-brain radiotherapy cohort, and 59 to the carmustine-thiotepa-autologous stem cell transplant cohort.
At a median follow-up of 21 months, 110 patients remain failure free, 32% from arm A, 54% from arm B, and 65% from arm C. Failure in 97% of the cases was due to primary site involvement, usually the brain.
Fifty-six percent of the patients are still alive, 39% in arm A, 59% in arm B, and 69% in arm C.
Ninety-seven patients died, 73 from lymphoma, 15 from toxicity of the first-line treatment, 2 from toxicity of the salvage regimen, 2 from neurotoxicity, and 5 from other causes.
Dr Ferreri concluded that the MATRIX regimen—the addition of rituximab and thiotepa to methotrexate and cytarabine—was associated with significant improvements in CR rate, ORR, and progression-free and overall survival.
The addition of rituximab and thiotepa did not increase toxicity, with the exception of greater hematologic adverse events, nor did the drugs increase the rates of severe complications. The agents also allowed for high rates of successful stem cell collection.