Primary central nervous system lymphoma (PCNSL) represents an aggressive subset of lymphoma exclusively affecting the CNS (brain parenchyma, spinal cord, eyes, cranial nerves and / or meninges).r Diffuse large B-cell lymphoma (DLBCL) comprises the majority (90%) of PCNSL.r Landmark prospective randomised clinical trials have led to the accepted standard of high-dose methotrexate chemotherapy, and later to the addition of high-dose cytarabine chemotherapy for the management of PCNSL.rrr
Rituximab has been shown to reduce CNS relapse from systemic DLBCL,r and evidence is now accumulating for a benefit with the addition of rituximab to standard methotrexate-containing treatment regimens.rrrr The evidence supporting this protocol is provided by a phase II multicentre international trial involving 52 patients with primary CNS B-cell lymphoma receiving rituximab, methotrexate, procarbazine and vincristine, followed by consolidation reduced-dose whole-brain radiotherapy (rdWBRT) and cytarabine.r
Between October 2002 and February 2009, 52 patients received five 14-day cycles of induction chemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV)r as follows:
- day 1, Rituximab 500 mg/m2; Day 2, Methotrexate 3.5 g/m2 (over 2 hours), vincristine 1.4 mg/m2; Days 1-7, Procarbazine 100 mg/m2/d (odd cycles only).
- patients who achieved a CR after five cycles received rdWBRT (23.40 Gy in 1.8-Gy fractions x 13) 3 - 5 weeks after chemotherapy completion.
- patients who achieved a PR after 5 cycles received another 2 cycles of R-MPV; If CR achieved after 2 further cycles then patients received rdWBRT (23.40 Gy in 1.8-Gy fractions x 13) 3 - 5 weeks after chemotherapy completion. If PR, SD or progression then patients offered WBRT (45 Gy in 25 fractions)
- following radiotherapy, all patients received two-consolidation high-dose cytarabine cycles (each cycle 28 days) comprising cytarabine 3 g/m2/d on days 1 and 2 of each cycle.
The primary end point was 2 year PFS in patients who received rdWBRT and secondary end points were objective response rate to R-MPV, overall response rate, OS, and neurocognitive outcome.
The R-MPV protocol has a high response rate and acceptable safety profile for the treatment of PCNSL. Similar results have been observed in a retrospective analysis of rituximab in addition with MPV or other combination chemotherapy protocols.r
Efficacy
Thirty-one patients (60%) achieved CR following 5 - 7 cycles of R-MPV and proceeded to rdWBRT. Of these, 2-year PFS was 77% and median PFS was 7.7 years. Median OS was not reached (with median follow up 5.9 years for survivors); 3 year OS was 87%. Overall median PFS was 3.3 years and median OS was 6.6 years. Following chemotherapy, cognitive assessment showed improvement in executive function (p<0.01) and verbal memory (p<0.05).r
Figure 1. CONSORT diagram showing treatment and outcome for all enrolled patients.
© Journal of Clinical Oncology 2013
Figure 2. Kaplan-Meier survival curves showing (A) OS and PFS for patients that received rdWBRT after achieving CR with 5 - 7 cycles of R-MPV; (B) PFS according to age for patients that received rdWBRT after achieving CR with 5 - 7 cycles of R-MPV; (C) Intent-to-treat OS and PFS for entire cohort; (D) Intent-to-treat PFS by age for entire cohort.
© Journal of Clinical Oncology 2013
Of 31 patients that received rdWBRT, 12 patients were progression-free and completed neuropsychological evaluations up to 48 months (median age 58 years). Baseline cognitive impairment was evident across several categories. Following induction chemotherapy (R-MPV), significant improvement in executive function (p<0.01) and verbal memory (p<0.05) were observed. No significant cognitive decline occurred during follow up except for motor speed (p<0.05) and memory performances fluctuated only mildly throughout the follow up period. Importantly, self-reported quality of life remained stable and there was no significant depressed mood observed.r
Toxicity
| |
Grade 3 |
Grade 4 |
Grade 5 |
| Renal |
1 |
- |
- |
| Febrile neutropenia |
NR |
NR |
3* (6%) |
| Pneumonitis |
- |
- |
1* |
|
Gastrointestional
- illeus
- perforated diverticulum
|
1 |
1 |
- |
Figure 3: Observed toxicities=grade 3 of all patients reported in the study (n=52).r NR not reported, *denotes same patient experienced grade 5 febrile neutropenia with pneumonitis. Regarding febrile neutropenia and other toxicities, an earlier interim report of the same study (n=30) previously reported by the same group revealed the following toxicities:
| |
Grade 3 |
Grade 4 |
Grade 5 |
|
Febrile neutropenia
pre G-CSF
amendment**
(n=5)
- post G-CSF
amendment**
- All (n=30)
|
- |
2 (40%)
1 (4%)
3 (10%)
|
1 (20%)
1 (3%)
|
| Renal |
1 (3%) |
- |
- |
| Anaemia |
3 (10%) |
- |
- |
| Thrombocytopenia |
8 (27%) |
- |
- |
| Lymphopenia |
12 (40%) |
- |
- |
Figure 4: Observed toxicities=grade 3 of all patients reported in the interim study report (n=30).r **Due to complications of febrile neutropenia in 2 of the first 5 treated patients, a protocol amendment was made to include GCSF 5µg/kg/d subcutaneously for 3-5 days with each cycle, starting 24 hours after last dose of procarbazine (odd cycles) and 96 hours after methotrexate or when methotrexate levels reached below 1x10-8mg/dL (even cycles).
It should be noted that in another independent retrospective analysis of rituximab in combination with differing chemotherapy regimens (n=121), 2 patients (2%) experienced grade 5 toxicity due to perforated viscera.r This appears to be a specific and recurrent complication affecting a small number of patients despite compliance with recommendations for pharmacologic gastric acid suppression within the protocol.r