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 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.rrrrr 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 radiation therapy (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 (max 2.8 mg);r days 1 - 7, procarbazine 100 mg/m2/d (odd cycles only).
- patients who achieved a complete response (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 partial response (PR) after 5 cycles received another 2 cycles of R-MPV. If CR achieved after 2 further cycles, patients received rdWBRT (23.40 Gy in 1.8-Gy fractions x 13) 3 - 5 weeks after chemotherapy completion. If PR, stable disease (SD) or progression, then patients offered WBRT (45 Gy in 25 fractions)
- following radiation therapy, all patients received two-consolidation high-dose cytarabine cycles (each cycle 28 days) comprising of cytarabine 3 g/m2/d on days 1 and 2 of each cycle.
The primary endpoint was 2-year progression-free survival (PFS) in patients who received rdWBRT, and secondary endpoints were objective response rate to R-MPV, overall response rate (ORR), overall survival (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 two retrospective analyses of rituximab in addition with MPV or other combination chemotherapy protocolsrr, whilst a single centre phase II study has demonstrated autologous stem cell transplantation as a viable alternative to WBRT. r
R-MPV can be safely delivered to older patients (i.e. > 60 years), including those over 80 years, and it appears to be superior to other therapies (i.e. methotrexate-temozolomide) in this age group.rr Outcomes in older patients have generally been poor (median PFS: 6.5 - 10 months, median OS: 7.9 - 31 months), but this may be reflective of a reduction in the total methotrexate dose in these studies as a recent large multicentre retrospective analysis has demonstrated that older patients (≥ 65 years) who complete methotrexate-based therapy (with minimal dose reductions) can achieve clinical outcomes similar to younger patients.rrr
Source |
Study & Year published |
Supports Use
|
Is the dose and regimen consistent with the protocol? |
Comments |
Phase II trials |
Shah et al. 2007r |
Yes |
Yes |
- |
Morris et al. 2013r |
Yes |
Yes |
- |
Omuro et al. 2015r |
Yes |
Yes. Followed by autologous stem cell transplantation. |
- |
Retrospective studies |
Hattori et al. 2017r |
Yes |
No. The dose of rituximab in R-MPV was reduced from 500 mg/m2 to 375 mg/m2 |
- |
Houillier et al. 2017r |
Yes |
No. Total number of methotrexate doses was 6. |
- |
Guidelines |
Date published / revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
NCCN |
December 2022 |
Yes |
Yes |
- |
BCCA |
- |
N/A |
N/A |
- |
CCO |
- |
N/A |
N/A |
- |
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.r
© Journal of Clinical Oncology 2013
Figure 2. Kaplan-Meier survival curvesr
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 who 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
Figure 3. Observed toxicitiesr
Toxicity
(n = 52)
|
Grade 3 |
Grade 4 |
Grade 5 |
Renal |
1 |
- |
- |
Febrile neutropenia |
NR |
NR |
3* (6%) |
Pneumonitis |
- |
- |
1* |
Gastrointestinal
- ileus
- perforated diverticulum
|
1 |
1 |
- |
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 in figure 4.
Figure 4. Haematological toxicityr
Toxicity
(n = 30)
|
Grade 4 |
Grade 5 |
Febrile neutropenia, pre G-CSF amendment**
(n = 5)
|
2 (40%) |
1 (20%) |
Post G-CSF amendment** |
1 (4%) |
1 (3%) |
All (n = 30) |
3 (10%) |
|
**Due to complications of febrile neutropenia in 2 of the first 5 treated patients, a protocol amendment was made to include GCSF 5 µg/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).
Figure 5. Observed toxicitiesr
Toxicity
(n = 30)
|
Grade 3 |
Grade 4 |
Grade 5 |
Renal |
1 (3%) |
- |
- |
Anaemia |
3 (10%) |
- |
- |
Thrombocytopenia |
8 (27%) |
- |
- |
Lymphocytopenia |
12 (40%) |
- |
- |
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